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Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina

ABSTRACT

I. INTRODUCTION

II. OVERVIEW OF MYOCARDIAL MATRIX AND REMODELING

A. Structure and Function of the Myocardial Matrix

B. Myocardial Remodeling in Myocardial Infarction

C. Myocardial Remodeling in Overload States

D. Myocardial Remodeling in Cardiomyopathic Disease

III. MYOCARDIAL MATRIX METALLOPROTEINASES

A. Taxonomy and Structure of the MMPs

B. Myocardial MMP Substrates

C. Transcriptional Regulation of MMPs

1. Modification of MMP transcription by prototypical stimuli

A) BIOACTIVE MOLECULES.

B) CYTOKINES.

C) MATRICELLULAR FACTORS.

D) GROWTH FACTORS.

2. Additional biological pathways to MMP transcription

3. Mechanical stimuli and MMP transcription

4. Integration of signals and MMP transcription

D. Translational/Posttranslational Modification of MMPs

E. The TIMPs

IV. MYOCARDIAL MATRIX METALLOPROTEINASES IN CARDIAC DISEASE

A. MMP Expression in Normal Adult Myocardium

B. MMPs in Myocardial Infarction

1. Human-based studies

2. Animal models

A) RODENT MODELS OF MI.

B) LARGE-ANIMAL MODELS OF MI.

C. MMPs in Overload States

1. Human-based studies

2. Animal models

D. MMPs in Cardiomyopathy

1. Human-based studies

2. Animal models

V. MYOCARDIAL MATRIX METALLOPROTEINASES: LESSONS FROM TRANSGENICS/GENETICS

A. Targeted Gene Deletion of MMPs

B. Targeted Gene Deletion of TIMPs

C. Myocardial Restricted Overexpression/Gene Transfer Studies

D. Gene Polymorphism Observations

VI. MYOCARDIAL MATRIX METALLOPROTEINASES: LESSONS FROM PHARMACOLOGY

A. Broad-Spectrum MMP Inhibition Studies

B. Selective MMP Inhibition Studies

C. Clinical Studies of MMP Inhibition

D. Therapeutic Interventions Affecting MMP Induction/Activation

VII. MONITORING MATRIX METALLOPROTEINASE LEVELS AND ACTIVITY

A. Plasma Profiling and Surrogate Markers

1. Plasma profiling post-MI

2. Plasma profiling in pressure overload

3. Plasma profiling in DCM and cardiovascular disease

3. Plasma profiling: limitations

B. Imaging MMP Activity

VIII. FUTURE DIRECTIONS AND CONCLUSIONS

A. Regulation of MMPs in Cardiac Disease

B. Defining the Role of MMPs: Novel Substrates and Function

C. The Myocardial Matrix as a Dynamic Entity Influencing Cardiac Form and Function

GRANTS

ACKNOWLEDGMENTS

REFERENCES

	ABSTRACT

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	I. INTRODUCTION

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Heart failure is a common cause of morbidity and mortality, and the incidence is increasing (115, 169, 177, 190, 260, 359, 465, 493). Following a specific cardiovascular stress, a cascade of compensatory structural events occurs within the myocardium and contributes to eventual left ventricular (LV) dysfunction and the manifestation of the heart failure syndrome. The cascade of structural events that occurs within the myocardium is highly complex, and therefore, for the purposes of this review, the focus will be on structural changes that occur within the myocardium in cardiac disease states such as myocardial infarction (MI), LV hypertrophy (LVH), or cardiomyopathic disease. In these instances, structural changes occur within the myocardial wall that result in changes in LV geometry, a process termed myocardial remodeling (7, 62, 75, 76, 102, 135, 209, 310, 335, 426, 429, 487, 494, 495). Myocardial remodeling is the summation of both cellular and extracellular processes, and a number of these processes have been the subject of past articles in Physiological Reviews (33, 49, 105, 225, 324, 390, 433). With respect to cellular processes, those that have been studied in detail include myocyte growth, apoptosis, and necrosis. With respect to the extracellular compartment and myocardial remodeling, a major clinical and basic research focus has been in the areas of vascular growth and patterning, as well as the conduction system. While historically considered a static structure, it is now becoming recognized that the myocardial extracellular matrix (ECM) is a complex microenvironment containing a large portfolio of matrix proteins, signaling molecules, proteases, and cell types that play a fundamental role in the myocardial remodeling process (28, 43, 52, 77, 78, 113, 134, 178, 183, 275, 303, 392, 486, 491, 535). Accordingly, the purpose of this review is to provide a brief overview of the myocardial ECM as it pertains to remodeling process in relevant cardiac disease states and then to examine in detail how the ECM undergoes remodeling through the induction and activation of a family of proteolytic enzymes, the matrix metalloproteinases (MMPs).

	II. OVERVIEW OF MYOCARDIAL MATRIX AND REMODELING

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A. Structure and Function of the Myocardial Matrix

The architectural complexity of the myocardium and the potential role that the ECM played in maintaining unique myocyte orientations throughout the LV free wall were described by Streeter and Basset (417, 418). Using a structural engineering approach, these authors demonstrated that myocyte orientation and myocardial fiber angles were highly organized and moved in a continuous fashion from the endocardium to the epicardium. It is the structural network of matrix proteins composed of proteins of highly organized structure and architecture, such as type I and type III collagen, that provide structural integrity to adjoining myocytes and contribute to overall LV pump function through the coordination of myocyte shortening. The architectural complexity of the myocardial ECM began to be appreciated through the use of scanning electron microscopy (2, 36, 488). These studies demonstrated the three-dimensional structure of the myocardial ECM and how the fibrillar weave surrounded and supported individual myocytes as well as fascicles of myocytes. Moreover, these initial studies demonstrated the complexity of the ECM and the structural interaction with the vascular compartment. Further research demonstrated that the myocardial ECM maintains alignment of myofibrils within the myocyte through a collagen-integrin-cytoskeleton-myofibril relation (50, 132, 254, 365, 367, 395, 398, 441). In addition to a fibrillar collagen network, a basement membrane, proteoglycans, and glycosaminoglycans, the myocardial ECM contains a large reservoir of bioactive molecules (17, 34, 41, 64, 89, 95, 101, 109, 111, 114, 188, 288, 360, 362, 492). For example, it has been demonstrated that the concentration of bioactive signaling molecules such as angiotensin II (ANG II) and endothelin (ET)-1 are over 100-fold higher within the myocardial interstitium than in plasma (89, 101, 288, 492). Moreover, cytokine activation and signaling such as that for tumor necrosis factor- (TNF) is highly compartmentalized within the myocardial interstitium (95, 111). Growth factors such as transforming growth factor- (TGF) are stored in a latent form within the myocardial interstitium and thereby form a reservoir of signaling molecules that directly influence myocardial ECM synthesis and degradation (67, 82, 218, 298, 399, 443). Moreover, mechanical stimuli such as stress or strain are likely transduced through the myocardial ECM to the cardiac myocyte, which in turn would directly affect myocyte growth (35, 37, 69, 217, 249–251, 313, 547). Thus structural changes that would occur within the myocardial ECM would in turn affect myocyte biology and the overall structure and function of the myocardium. As such, a number of studies have examined compositional and structural changes that occur within the myocardial ECM following the induction of a hypertensive stimulus, following myocardial injury such as with MI, and in cardiomyopathic disease. The specific and unique changes to the myocardial ECM as it pertains to these cardiac disease states are examined in the subsequent sections. This examination is not intended to be comprehensive, but rather to provide the foundation for a more in-depth review of a specific proteolytic pathway that contributes to myocardial ECM remodeling in relevant cardiac disease processes.

B. Myocardial Remodeling in Myocardial Infarction

A number of cellular and extracellular factors contribute to the complex process of myocardial remodeling following MI. Specifically, myocyte loss, hypertrophy of remaining myocytes, and increased size and number of nonmyocyte cells all contribute to changes in LV myocardial wall geometry. Significant alterations in the structure and composition of the myocardial ECM occur following MI (75, 76, 166, 182–185, 192, 205, 226, 251, 270, 313, 350, 392, 426, 432, 434, 468, 473, 474, 487, 491, 496, 497, 543, 547). Cardiac wound repair after MI involves temporarily-overlapping phases, which include an inflammatory phase and tissue remodeling phase. The first phase starts after coronary artery occlusion with or without reperfusion and involves degradation of normal ECM, invasion of inflammatory cells at the site of initial injury, and the induction of bioactive peptides and cytokines. Degradation of the ECM during the acute phase is considered to be an essential event that allows for the ingress of inflammatory cells as well as proliferation and maturation of macrophages and fibroblasts, and provides the necessary substructure for scar formation. In 1916, macroscopic/microscopic studies by Karsner and Dwyer (192) reported an early (within 24 h) disappearance of the normal collagen matrix within the infarcted myocardium, which was then followed by significant matrix deposition. However, the mechanisms which caused this early loss of myocardial ECM within the MI region followed by ECM synthesis and deposition remained elusive. In serial studies utilizing biochemical and computer-assisted morphometric techniques, several laboratories reported a loss of normal collagen strut formation, increased release of hydroxyproline (an amino acid primarily found in collagen), and reduced collagen cross-linking within the ischemic region very early post-MI (76, 166, 182, 184, 185, 226, 270, 350, 426, 432, 434, 468, 474, 496, 497, 535, 543). These early ECM events occurred prior to the egress of inflammatory cells into the MI region. For example, in a study by Judd and Wexler (182), an early reduction in hydroxyproline content occurred following myocardial injury in rats, which was then accompanied by increased hydroxyproline during longer time periods (Fig. 1). These reports speculated that the release of endogenous enzymes was responsible for the initial degradation of the myocardial ECM in the early post-MI period, which was then followed by a vigorous inflammatory response that amplified collagen proteolytic activity. Indeed, an early study by the Factor laboratory reported that by 3 h post-MI, the decrease in collagen integrity was accompanied by increased proteinase activity (434). In this early time period, LV myocardial ECM degradation and remodeling were associated with an increased probability of rupture (226). Thus dynamic changes occur within the myocardial ECM in the initial and early phases of the post-MI period, that directly affect the mechanical properties of the LV myocardium. As the MI period progresses over the next several days, an influx of inflammatory cells into the injured myocardium occurs which results in further proteolysis of cellular and ECM proteins. In addition, this inflammatory response causes proliferation and differentiation of fibroblasts and other interstitial cells, and the elaboration of bioactive molecules which contribute to a robust synthesis of ECM for the purposes of scar formation (23, 75, 76, 113, 114, 155, 266, 303, 383, 426, 491). These changes within the MI region yield distinctive cellular and extracellular phenotypic changes. For example, the differentiation and proliferation of fibroblasts within the MI region demonstrate a unique protein signature and function to not only synthesize ECM proteins critical for scar formation, but also contribute to the biophysical properties of the scar itself and have been termed myofibroblasts (34, 55, 75, 76, 114, 195, 331, 491, 499, 522, 547). Early studies utilizing corticosteroids demonstrated the importance of this inflammatory response with respect to scar formation and maturation (205, 473). However, it remains unclear if the exuberant release of proteolytic enzymes from inflammatory cells and myofibroblasts which occur during the initial MI wound healing response are critical for scar maturation.

View larger version (12K): [in this window] [in a new window]   FIG. 1. Myocardial hydroxyproline content, reflective of fibrillar collagen content, initially fell from reference control values following isoproterenol-induced myocardial infarction (MI) as shown by the open arrow. Myocardial hydroxyproline increased by day 7 (closed arrow) and increased further by 2 wk post MI. This demonstrated that collagen degradation precedes collagen accumulation and scar formation following MI. [From Judd and Wexler (182).]

C. Myocardial Remodeling in Overload States

Two distinct patterns of LVH occur in response to a persistent load: pressure overload hypertrophy (POH) and volume overload hypertrophy (VOH). Changes in LV wall stress patterns, which are uniquely different in POH and VOH, likely drive the adaptive hypertrophic response. POH results in a concentric hypertrophy whereby wall thickness is increased while LV diameter remains the same or is decreased. A myocyte undergoes concentric hypertrophy by adding sarcomeres in parallel to achieve an increase in width. In contrast, VOH results in an eccentric hypertrophy whereby wall thickness remains the same or is decreased while LV diameter increases. Eccentric hypertrophy involves the addition of sarcomeres in series to achieve an increase in myocyte length. While in both forms of LVH, alterations in loading conditions form the central mechanical stimulus, local elaboration of growth factors such as TGF, and neurohormonal factors as such as ANG II and ET can modify the growth response, and have particular relevance to the ECM (2, 12, 34, 35, 41, 64, 132, 134, 217, 249, 250, 337, 373, 404, 441, 486, 488, 535). Specifically, since TGF, ANG II, and ET have all been demonstrated to induce increased collagen synthesis in vitro, then it follows that amplification in the formation and/or signaling of these bioactive molecules in vivo would lead to increased ECM accumulation with POH. Indeed, a structural hallmark of prolonged POH is significantly increased collagen accumulation between individual myocytes and myocyte fascicles. The extent and degree of ECM remodeling with POH were clearly exemplified by the landmark studies by Weber and Janicki (2, 488). As shown in Figure 2, these past studies demonstrated thickening of the collagen weave and overall increased relative content between myocytes in a nonhuman primate model of POH. While the accumulation of ECM with POH is not exclusive to collagen, these initial structural studies gave rise to the generic term for this extracellular remodeling process as myocardial fibrosis. In POH, the accumulation of ECM and eventual myocardial fibrosis significantly contributes to LV function. In particular, enhanced synthesis and deposition of myocardial ECM is directly associated with increased LV myocardial stiffness properties, which in turn causes poor filling characteristics during diastole (12, 35, 159, 191, 194, 312, 314, 421, 488). Indeed, recent clinical evidence suggests that progressive ECM accumulation and diastolic dysfunction are important underlying pathophysiological mechanisms for heart failure in patients with POH (196, 544, 545). In contrast to POH, LV end-diastolic volumes increase in VOH due to the persistently elevated preload, and as a result, a much different pattern of ECM remodeling occurs. In large-animal models of VOH due to chronic mitral regurgitation, the LV remodeling process is accompanied by a distinctive loss of collagen fibrils surrounding individual myocytes (88, 330, 409, 450). These changes in ECM support are associated with changes in isolated LV myocyte geometry where the cardiac cells increase in length. Representative scanning electron micrographs taken from a well-established model of canine mitral regurgitation (88, 409) are shown in Figure 3 and demonstrate the profound differences in ECM structure and composition compared with normal myocardium and that of POH. In rodent models of aortocaval fistula, another form of VOH, a similar pattern of LV remodeling and changes in the ECM structure and composition have been reported (96, 124, 127, 244, 274, 484). In both forms of LVH, a loss of normal ECM structure and function occurs which suggests that alterations in ECM degradative processes have occurred. With POH, the highly organized architecture of the ECM is replaced with a thickened, poorly organized ECM. Thus initial degradation of the normal ECM likely occurs with POH, which is then followed by decreased capacity for ECM degradation and turnover. In VOH, increased ECM proteolytic activity likely contributes to the reduced ECM content and support and thereby facilitates the overall LV remodeling process. Proteolytic enzymes that likely contribute to the ECM remodeling with LVH are reviewed in a subsequent section.

View larger version (181K): [in this window] [in a new window]   FIG. 2. Scanning electron micrographs taken from normal nonhuman primate left ventricular (LV) myocardium and following the induction of pressure overload hypertrophy (POH). These microscopic studies demonstrated thickening of the collagen weave and overall increased relative content between myocytes with POH. [From Abrahams et al. (2).]

View larger version (133K): [in this window] [in a new window]   FIG. 3. Representative scanning electron micrographs taken from normal canine LV myocardium and following chronic mitral regurgitation that causes a volume overload hypertrophy (VOH). In this well established model of VOH (88, 330, 409, 450, 484), a loss of normal ECM architecture was demonstrated between individual myocytes (arrows), and the collagen supporting network is poorly organized. (Figure kindly provided by Dr. Louis Dell'Italia, University of Alabama at Birmingham.)

The dilated cardiomyopathies are a classification of primary myocardial disease states which constitute a significant proportion of patients with heart failure (167, 341, 510). While the etiologies for dilated cardiomyopathy (DCM) are diverse, a general pathophysiological classification scheme has been developed and termed ischemic, idiopathic (nonischemic), or infectious. The pathophysiology of DCM is that an increase in LV ventricular chamber radius to wall thickness occurs which results in increased myocardial wall stress. This increased LV myocardial wall stress in turn can promote further dilation. Significant changes in the myocardial ECM occur with cardiomyopathic disease and likely facilitate this remodeling process (104, 146, 206, 326, 391, 489). Within the myocardial ECM, alterations in the myocardial fibrillar collagen architecture have been reported in patients with DCM. For example, morphometric studies have identified a reduction in the number and conformation of collagen struts between adjoining myocytes in samples taken from patients with DCM (104, 489). However, the extent and type of ECM remodeling which occurs with DCM is variable and is likely dependent on the underlying etiology. For example, in idiopathic DCM, the alterations in normal ECM architecture are associated with reduced collagen cross-linking, which will make the ECM more susceptible to degradation (146, 206). Animal models of pacing-induced DCM have demonstrated a time-dependent alteration in normal ECM structure and composition that is accompanied by the progressive changes in LV geometry and function (208, 410, 490, 537). Specifically, in this model of DCM, the progressive loss of normal myocardial ECM is accompanied by LV myocyte lengthening and a loss of myocyte adhesion to critical ECM components (208, 537). These early changes in myocardial ECM structure and composition likely contribute to the progression of LV dilation and dysfunction in this nonischemic model of DCM. In ischemic DCM, large areas of ECM accumulation, that is, focal areas of myocardial fibrosis, are accompanied by other areas of the myocardium in which ECM content and composition are reduced. For example, in an animal model of ischemic DCM created by repeated coronary embolizations, areas of collagen accumulation are accompanied by localized areas of collagen loss (156, 375). Thus a heterogeneous pattern of ECM remodeling occurs in ischemic DCM where enhanced ECM accumulation and degradation occur simultaneously. In cases of infectious DCM, the robust inflammatory response within the myocardium heralds the induction of cytokine and growth factor receptor pathways which can augment ECM synthesis and accumulation (71, 221, 228, 325, 372). Using a selective corrosive technique which reveals the collagen skeletal framework amenable for scanning electron microscopy, Rossi (368) demonstrated that significant ECM remodeling occurred in patients with DCM secondary to Chagastic myocarditis (221). Representative scanning electron micrographs of a normal specimen and one taken from a patient with Chagas' disease are shown in Figure 4. In this form of DCM, the normal myocardial collagen matrix was replaced by a poorly structured, emphysematous matrix between areas of adjacent myocytes and myocardial fascicles. In animal models of infectious/inflammatory DCM commonly induced by viral injections, a similar pattern of ECM degradation paralleled by a abnormal ECM accumulation and structure have been reported (228, 372). While the specific pattern of ECM remodeling is as diverse as the etiologies which give rise to the spectrum of cardiomyopathic disease, some commonalities do exist. First, there is a destruction of the normal ECM framework in terms of structural protein content and architecture. It is likely that this loss in ECM support contributes to the progressive LV dilation and dysfunction that are common pathophysiological underpinnings for DCM. Second, in patients with DCM, there is a heterogeneous and continuous cycle of ECM synthesis and accumulation as well as ECM degradation which occur within myocardium in a regional specific manner. Due to the fact that severe DCM is the most common clinical presentation for cardiac transplantation, a number of studies have been performed on the explanted myocardial specimens and identified ECM proteolytic pathways that likely contribute to the ECM remodeling process. These studies are reviewed in detail in a subsequent section.

View larger version (104K): [in this window] [in a new window]   FIG. 4. Representative scanning electron micrographs of a normal human LV myocardial specimen and one taken from a patient with Chagas' disease. In these micrographs, the cardiac cells have been digested using a corrosive technique (368). With the use of this approach, the complexity and three-dimensional aspects of the human myocardial ECM can be readily appreciated. In dilated cardiomyopathy secondary to Chagas' disease, a dense poorly organized matrix that has an emphysematous appearance (arrows) can be seen. [From Rossi (368).]

	III. MYOCARDIAL MATRIX METALLOPROTEINASES

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A. Taxonomy and Structure of the MMPs

A great deal of confusion can surround the nomenclature of MMPs, due to the fact that initially MMPs were named based on recognized substrates. However, as detailed in a subsequent section, a large and diverse portfolio of substrates exists for MMPs, and a great deal of crossover exists between substrates and MMP types. Table 1 provides the taxonomy number, generic and commonly used group names, and approximate molecular weights for MMP types that have thus far been identified to exist within the myocardium. However, substrate portfolios for specific MMPs are not provided, since active research is occurring in this area, and therefore, any attempt to compile such a list would need to be considered incomplete or obsolete. The generic or common names can be a source of confusion, and therefore, the specific MMP type under question is often referred to by number. For example, MMP-13 has been referred to as rodent collagenase, since this is the primary collagenase found in rodent myocardial samples (96, 227, 228, 334, 504). However, robust levels of MMP-13 have been reported in large animal and human myocardial specimens (39, 348, 503). MMP-8 has been commonly called neutrophil collagenase; however, this MMP type has localized to a number of cell types including fibroblasts and smooth muscle cells (1, 118, 355, 403, 405). Thus, while relatively high levels of specific MMPs may be found in certain tissue types or cells, all of the MMPs shown in Table 1 can be expressed by the major cell types found within the myocardium: cardiac myocytes, fibroblasts, smooth muscle cells, endothelial cells, and macrophages.

While the MMPs were initially considered to be secreted in a soluble, proenzyme form, a unique subfamily of MMPs initially described by Sato and colleagues in 1994 were discovered to be membrane bound (378). These membrane-type MMPs (MT-MMPs) of which MT1-MMP is the most well characterized, are a fully active enzyme once inserted into the cell membrane and contains an extracellular catalytic domain, a transmembrane domain, and an intracellular domain, all of which are critical for full functioning of the protease (224, 317, 353, 378). It has been demonstrated that trans-Golgi processing and intracellular activational steps, such as those by the intracellular protease furin, play a critical role in processing the mature, full-length MT1-MMP (148, 327, 378). Thus, unlike the secretable MMPs, MT-MMPs are inserted into the cell membrane already activated and therefore can serve as a localized, pericellular site of ECM proteolytic activity.

B. Myocardial MMP Substrates

Several comprehensive reviews using artificial substrates and computer-based modeling have been completed and emphasize the diversity of MMP substrates (170, 321, 413, 452). For the purposes of this review, those substrates that hold potential relevance to the myocardium will be identified. The interstitial collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase-3 (MMP-13) possess high substrate specificity for fibrillar collagens, as well as other ECM proteins such as aggrecan, perlican, versican, and proteoglycans. The gelatinases (MMP-2 and MMP-9) demonstrate substrate affinity for denatured fibrillar collagen, basement membrane proteins such as collagen type IV, fibronectin, and laminin. MMP-2 and MMP-9 also exhibit proteolytic activity against elastin and proteoglycans. The substrate portfolio for stromelysin (MMP-3) includes all basement membrane proteins, elastin, and proteoglycans. MMP-7 appears to have a wide substrate portfolio that may be due to the fact that this MMP type lacks the hemopexin domain and therefore may lack critical substrate recognition/docking sites (472). MMP-7 possesses proteolytic activity against the fibrillar collagens I and III, basement membrane proteins (collagen IV, fibronectin), and proteoglycans. One of the more proteolytically diverse MMP types is the MT-MMPs, where for example MT1-MMP can degrade all fibrillar collagens, all basement membrane components, ECM proteins such as perlican and versican, and the chondroitin sulfates.

Another important proteolytic feature of MMPs is that other pro-MMPs also serve as substrates. This results in the ability of one active MMP type to induce proteolytic activation of other MMPs (507). One of the first to be recognized for this particular function was stromelysin, MMP-3 (431, 506). MMP-3 participates in the activational cascade by forming intermediary complexes with other pro-MMPs, ultimately yielding a fully active MMP. For example, Murphy and colleagues reported a 12-fold increase in the conversion of pro-MMP-1 to active MMP-1 in the presence of MMP-3 (290). An emerging body of evidence suggests that a fundamental mechanism for MMP-2 activation is through proteolytic cleavage by MT1-MMP (207, 290, 297, 419). In this activational pathway, pro-MMP-2 is "presented" to MT1-MMP, and the prodomain is cleaved yielding a fully active MMP-2. In addition, it is likely that MT1-MMP processes other pro-MMPs, such as pro-MMP-13 (431). Thus, while further research is required to identify the extent and conditions under which these localized MMP activational cascades would occur, this process would provide a means for a significant and localized amplification of ECM proteolytic activity.

There is emerging evidence to suggest that MMPs can also degrade nonmatrix substrates such as cytokines, bioactivate peptides, and growth factors, which in turn would affect a number of biological processes within the myocardium (125, 170, 210, 213, 222, 280, 306, 309, 318, 413, 435, 463, 500, 523). For example, MT1-MMP and MMP-7 have both been identified to process membrane-bound TNF- to a soluble form (125, 213). Angiostatin, a small bioactive peptide which can modulate the effects of vascular endothelial growth factor (VEGF), can be formed by MMP processing (500). In more recent studies, it has been demonstrated that MMP-3, MMP-7, MMP-9, and the MT-MMPs can proteolytically process VEGF and therefore modify the local biological activity of this growth factor (210, 302, 500). Other growth factors, such as the release of active insulin-like growth factor, can be mediated by several MMP types (256, 276, 299, 508, 541). Thus it is likely that a number of important nonmatrix MMP substrates exist which hold relevance to the LV remodeling process.

C. Transcriptional Regulation of MMPs

Transcriptional activity is an important event in the ultimate synthesis and release of soluble MMPs as well as the MT-MMPs within the myocardium. Following either biological and/or mechanical stimuli, a cascade of intracellular events culminates in the formation of a number of transcription factors. These transcription factors can bind to the promoter region of MMP genes and induce transcription. A generalized schematic for transcription factor binding sites within representative MMP promoter regions are shown in Figure 5, which was adapted from several generalized reviews on this subject (20, 59, 110). Two major cis-acting elements are found in a majority of the MMP promoters: activator protein-1 (AP-1) and polyoma enhancer A binding protein-3 (PEA-3) which interact with the Fos and Jun family and Ets family of transcription factors, respectively. MMP-2 is interesting in that it lacks both the AP-1 and PEA-3 elements, and also lacks a TATA box (20). Due to the fact that MMP-2 lacks these canonical transcription factor binding sites, it was originally assumed that MMP-2 was constitutively expressed and under limited transcriptional regulation. While indeed MMP-2 has been demonstrated to be constitutively expressed in tissues at substantial levels, there is evidence that external stimuli can influence an additional increase in MMP-2 production (215, 261). While AP-1 and PEA-3 are found in most MMP types, there are other elements found in individual MMP promoter regions. For example, MMP-1, MMP-7, MMP-13, and MT1-MMP all have one or more TGF inhibitory elements (TIEs) which bind the family of SMAD transcription factors (84, 110, 150, 234, 245, 462). Other transcription factors such as SP1 likely bind to the GC box contained within the promoter regions of MMP-2, MMP-9, and MT1-MMP (20, 245). In addition, MMP-9 has a nuclear factor-B (NF-B) binding site (110, 308). MMP-1 and MMP-13 both have been described to have an NF-B-like binding site which responds to the NF-B transcription factor (470). Thus the transcription factor binding sites, the number of these binding sites, and the type of upstream stimuli that are operative under certain cardiac disease states will ultimately determine the transcriptional activity of select MMP types. It is this level of transcriptional regulation that likely adds regional specificity to MMP induction within the myocardium. Specific examples of how specific signaling cascades, known to be operative within the myocardium, can influence MMP transcriptional activity are discussed in the following paragraphs.

View larger version (79K): [in this window] [in a new window]   FIG. 5. Transcription factor binding elements located within the proximal promoters of representative matrix metalloproteinase (MMP) types. C/EBP-, CCAAT enhancer-binding protein; TIE, transforming growth factor- inhibitory element; AP-1, activator protein-1; PEA-3, polyoma enhancer A binding protein-3; OSE-2, osteoblastic cis-acting element; TATA, TATA box; AP-2, activator protein-2; Sil, silencer; GC, Sp-1 binding site; NF-B, NF-B binding site; CCAAT, CCAAT box; SPRE, stromelysin-1 platelet-derived growth factor responsive element.

A) BIOACTIVE MOLECULES.  ANG II is an important mediator in the myocardial remodeling process associated with MI, LVH, or DCM. ANG II receptor activation ultimately causes the induction of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathways. Transcription factors activated by this pathway include the AP-1 family of transcription factors, STATs and NF-B. Thus it would be anticipated that ANG II receptor activation would potentially cause activation of MMPs. Indeed, exposure of ANG II in cell culture systems causes a concordant induction of transcription factors that would bind to MMP promoter regions and increased MMP levels (22, 45, 180, 471, 480). For example, Wang et al. (480) reported that stretch-induced induction of MMP-2 and MT1-MMP was abrogated by coincubation with an ANG II receptor antagonist. In an early study by our laboratory, it was reported that exposure of isolated cardiac myocytes to a fixed concentration of ANG II caused a robust increase in MMP-2 levels as assessed by gel zymography (79). It should be recognized that zymography entails the use of detergents during the extraction phase and during electrophoresis. This results in unfolding of the MMP structure and thereby exposes the catalytic domain of the proenzyme. As a consequence, both the proform and the active form of MMPs can be visualized using this substrate zymographic approach. In the next set of studies, ANG II stimulation of neonatal rat ventricular myocytes triggered the mobilization of cytoplasmic NF-B to the nucleus, which in turn increased MMP-9 transcription (371). STAT proteins have been demonstrated to participate in the ANG II-mediated transduction pathway as well. However, there is a considerable amount of cross-talk and feedback between receptor pathways, and the initial increase in MMP levels that can be induced by ANG II may not be sustained or, in fact, may actually be suppressed by prolonged exposure. For example, stimulation of rat cardiac fibroblasts with ANG II induced the production of both NF-B and AP-1 transcription factors, and this was associated with an increase in collagen type-1 production as well as a decrease in MMP-1 expression (63). A study by Chen et al. (68) demonstrated that STAT1- and STAT3-mediated ANG II induced factors that would inhibit MMP activity in human proximal tubular epithelial cells, suggesting a role in the fibrotic process. Indeed, it is likely that ANG II receptor activation induces TGF, which in turn causes multiple effects on MMP transcription, which is discussed in greater detail in a subsequent paragraph. Very often the production of ANG II is paralleled by increased levels of aldosterone. While it has been identified that myocardial overexpression of aldosterone induces production of fibrotic proteins such as collagen (87, 342), whether and to what degree aldosterone influences MMP transcription directly remains unknown. There is no direct evidence to date to suggest that a MMP promoter region contains a hormone response element (HRE) (389). Although it has been demonstrated that other steroids can modulate MMP expression, the effects of these steroids on the transcriptional regulation are likely due to indirect mechanisms of action (94, 223). Nevertheless, since decades of research have clearly demonstrated that ANG II and aldosterone contribute to adverse myocardial remodeling, most notably myocardial fibrosis, to what degree and by what mechanisms these signaling molecules affect MMP transcription warrant further study.

ET is another bioactive molecule that likely contributes to the adverse myocardial remodeling process. One intracellular event following ET receptor activation is to activate members of the protein kinase C (PKC) family. These activated PKC isotypes ultimately lead to the activation of transcription factors such as c-Jun, GATA-4, a member of the Ets family, and NF-B, which in turn could lead to MMP transcriptional activation (295, 296, 424). For example, ET increased MMP-1 levels in vascular endothelial cell cultures and MT1-MMP levels in cardiac myocyte preparations (79, 296). In a study by Tsurdua et al. (449), it was demonstrated that ET exposure could amplify the release of MMPs in a myocardial fibroblast preparation. Furthermore, Podesser et al. (338) demonstrated that ET receptor inhibition attenuated the degree of MMP levels in an intact mouse model of MI.

Increased synthesis and release of the catecholamine norepinephrine (NE) has been considered a biological hallmark of heart failure progression (112, 198). Thus increased levels of a number of signaling molecules such as ANG II and ET in the context of myocardial remodeling and heart failure are likely due, at least in part, to systemic neurohormonal activation and the elaboration of NE. NE infusion in rats resulted in an increased MMP-2 mRNA 3 days post infusion (42). In addition to the indirect effects of NE on MMP transcription, it is likely that NE can directly influence MMP transcription through activation of the - and -receptor pathways (79, 393). Thus whether the effects of catecholamines on MMP transcription are directly related to the actions of NE, or whether other bioactive molecules are involved remains to be determined.

B) CYTOKINES.  While a number of cytokines/chemokines have been identified in the myocardial remodeling process, for the purpose of this review TNF and interleukin (IL)-1 will be presented as prototypical examples. While the TNF signaling cascade is divergent and can evoke multiple pathways, activation of the mitogen-activated protein kinases (JNK and p38) and formation of the transcription complexes of the AP-1 family and NF-B are common events (16). Thus it follows that TNF would modify MMP transcription and ultimately myocardial MMP levels. Cardiac-specific overexpression of TNF in transgenic mice caused progressive myocardial remodeling and was temporally associated with MMP induction (399). In another transgenic construct, cardiac restricted overexpression of TNF and disruption of NF-B signaling directly altered MMP mRNA levels (197). Specifically, with TNF overexpression only, MMP-9 increased, whereas with the TNF overexpression and disrupted NF-B, MMP-9 levels were significantly attenuated (197). Other in vitro studies demonstrated that TNF induced MMP-13 and that this induction was reduced by both AP-1 and NF-B inhibitors (232). The proinflammatory cytokine IL-1, through its cognate receptor, can cause activation of the NF-B pathway as well as the AP-1 family of transcription factors (246, 257). For example, IL-1 has been demonstrated to increase both NF-B and AP-1 DNA binding in neonatal rat myocytes (246). Using myocardial fibroblast cultures, Siwik and colleagues (246, 400) provided conclusive measurements that TNF as well as IL-1 could stimulate the de novo production of certain MMP types. In these studies, relative levels of MMP-2 and putatively MMP-9 were increased in the conditioned fibroblast media with exposure to TNF or IL-1 when examined by gelatin zymography (Fig. 6). In other studies, stimulation of adult rat cardiac fibroblasts with IL-1 induced an upregulation of both MMP-2 and MMP-9 protein levels, which was reduced with NF-B inhibition (511). Additionally, MMP-1 levels increased following IL-1 stimulation and were effectively attenuated with mitogen-activated protein kinase inhibitors (200). These studies provide a clear cause-effect relationship between cytokine stimulation and MMP transcriptional activity. Moreover, it is likely that IL-1 and TNF cause induction of specific MMP types through both NF-B-dependent and -independent pathways.

View larger version (28K): [in this window] [in a new window]   FIG. 6. Effects of inflammatory cytokines on MMP release in conditioned media of cultured myocardial fibroblasts. MMP levels were assessed by zymography, and therefore, the identity of MMP types was estimated from molecular weights shown on the left. Zymography entails treatment of the myocardial extracts with detergent that will unfold the MMP structure causing exposure of the catalytic domain. Thus a proteolytic band corresponding to both the proform and active form of MMPs will be visualized by this technique. Annotations of likely MMP types revealed by zymography are indicated on the right. The high molecular weights likely reflect dimerization and binding of MMPs, whereas molecular weights around the 90-kDa region likely reflect MMP-9, those around the 70-kDa region reflect MMP-2, and those at lower molecular weights likely reflect MMP-13. Fibroblasts were exposed to interleukin (IL)-1 (4 ng/ml), tumor necrosis factor (TNF) (100 ng/ml), IL-6 (10 ng/ml), or interferon- (500 U/ml). The cytokines IL-1, TNF, and IL-6 caused a significant increase in MMP levels that was likely due to increased formation of transcription factors which bind to MMP promoters and in turn increased MMP transcription. [From Siwik et al. (400).]

Past studies have demonstrated that OPN can induce MMP-2 and MMP-9 activation through an NF-B-dependent mechanism (336, 345, 513). Conversely, it has been shown that OPN can reduce IL-1-mediated induction of MMP-1 in adult rat cardiac fibroblasts (513). TSPs are a family of secreted glycoproteins that appear to modulate cell-matrix interactions through the coalescence of membrane proteins and signaling molecules at specific contact points on the cell surface. TSP-2 and TSP-4 have been shown to be upregulated in the transition from myocardial hypertrophy to failure in renin overexpressing rats and spontaneously hypertensive rats, respectively (374, 388). In addition, TSP-2 null mice show abnormalities in matrix structure and composition (521). TSP signaling likely involves mitogen-activated protein kinase and ultimately the formation of AP-1 transcriptional complexes (48, 97, 137). Although it is not yet known what the direct effects of TSP are on MMP transcription, fibroblasts isolated from TSP-2 null mice demonstrated abnormal ECM adhesion and increased levels of MMP-2 (521). In addition, TSP fragments stimulated differential production of MMP-2 and MMP-9 in bovine endothelial cells (97). In light of the fact that these matricellular signaling proteins are produced within the adult myocardium following a period of cardiovascular stress, it is likely that these play a role in MMP transcription as well as contribute to the overall ECM remodeling process.

D) GROWTH FACTORS.  The TGF superfamily consists of a large number of growth-signaling proteins, but for the purpose of this review, TGF will refer to the most abundant and well-studied member TGF-1. Heightened TGF signaling has been implicated to contribute to myocardial and ECM growth following MI and with pressure overload hypertrophy (POH) (364). TGF can bind to a number of receptor complexes, and through a series of translocations, ultimately results in phosphorylation of a unique set of intracellular signaling proteins, the SMADs. Through a series of SMAD interactions, eventual binding to the TIE promoter region occurs, and given that MMPs-1 and -7 as well as MT1-MMP contain TIE binding domains, it is suggestive that these MMP types would be altered with increased levels of TGF. Since TGF is classically considered a "profibrotic" molecule, it was assumed that TGF would inhibit MMP transcription, and thereby reduce ECM turnover. Indeed, a number of studies demonstrated that TGF could reduce MMP transcription (150, 152, 233, 462, 532). A study by Hall et al. (150) demonstrated that the proximal AP-1 site is essential for the TGF-mediated repression of MMP-1 in cultured fibroblasts. In another study using dermal fibroblasts, it was demonstrated that MMP-1 transcriptional suppression was mediated through the SMAD3 and SMAD4 activation (532). It has also been demonstrated that SMADs can directly interact with members of the AP-1 family of transcription factors (233, 516). Therefore, while TGF may inhibit MMP transcription through the SMAD pathway, simultaneous activation of transcription factors that will induce certain MMP types can occur. For example, TGF can stimulate MMP-13 transcriptional activity through the activation of Fos and Jun transcription factors (462). Moreover, other studies have demonstrated that TGF can activate other transcriptional complexes, such as the Ets family of transcription factors (84), which would also induce certain MMP types. Thus it is likely that TGF causes a duality of responses with respect to MMP transcriptional activity which are likely to be concentration, cell, and time dependent.

2. Additional biological pathways to MMP transcription

A novel transmembrane protein has been identified that induces the expression of specific MMPs in vitro (29, 56, 149, 289, 339, 446, 518). The nomenclature of this protein has varied somewhat (Basigen, collagenase stimulatory factor, CD147) but has most commonly been identified as the extracellular matrix metalloproteinase inducer protein (EMMPRIN) (29, 56). The most active area of EMMPRIN investigation has been with respect to tumor growth, where increased EMMPRIN expression has been localized to the area with intense remodeling activity or highly invasive tumors (29, 56, 289, 339, 446, 518). In this pathological tissue remodeling process, it is likely that EMMPRIN is a contributory factor in the stimulation of MMPs required for tumor invasion and metastasis. Our laboratory identified that robust levels of EMMPRIN exist within the human myocardium and increase significantly with end-stage DCM (406). Moreover, increased EMMPRIN levels have been associated with ECM remodeling and atherosclerotic plaque progression and in monocytes in patients post-MI (386, 530). Furthermore, EMMPRIN caused an induction of MMP types in vascular smooth muscle cell cultures (386). Therefore, EMMPRIN may be an important factor in the transcriptional regulation of MMPs in the context of myocardial remodeling.

Cardiovascular disease states such as ischemia-reperfusion and MI are often associated with oxidative stress and the formation of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. Increased ROS production can have multiple effects, which include direct modification of proteins-posttranslational modification, directly inducing intracellular factors that can modulate MMP transcription, as well as the induction of signaling molecules such as cytokines which in turn will alter MMP transcription. Thus oxidative stress and the formation of ROS cause the activation of MMPs through two primary mechanisms: posttranslational modification of pro-MMPs to an active form which will be discussed in a subsequent section, and the formation of transcriptional complexes which will yield newly formed MMP species (121, 303, 387, 401, 402, 478, 483). Studies in several laboratories have demonstrated a direct relationship between the formation of ROS and the induction of MMPs in the context of ischemia/reperfusion and cardiac surgery (181, 235, 268, 269). Moreover, in vitro studies have demonstrated that direct exposure of ROS will induce MMP release (19, 72, 536). For example, a brief incubation of hydrogen peroxide in cardiac fibroblasts increased MMP levels (402). In other studies, exposure of endothelial cells to hydrogen peroxide caused the induction of MMP-2 and MT1-MMP (19). Increased nitric oxide levels, which can also induce reactive species, have been shown to increase MMP-13 mRNA levels in a vascular endothelial cell preparation (536). Since oxidative stress does not occur in isolation, but rather in the context of a number of signaling events, it would follow that heightened ROS or reactive nitrogen levels could potentially synergize MMP transcription. However, future studies will be necessary to dissect out and differentiate the effects of oxidative stress in regard to MMP transcriptional and posttranslational effects.

3. Mechanical stimuli and MMP transcription

Perhaps the most underappreciated and understudied mechanism for the regulation of MMP transcription is that of mechanical stimuli. Since the ECM is integrated to the intracellular compartment through a series of transmembrane proteins, the integrins, it is likely that changes in mechanical stress placed on the myocardium would alter intracellular signaling pathways involved in MMP transcriptional activity (51, 249, 356, 366, 373, 396, 448). Increased transmural pressure increased relative MMP-2 and MMP-9 levels using an ex vivo arterial preparation (70). In a cell culture system of dynamic tensile strain, increased mRNA levels for several classes of MMPs were documented, which appeared to be time dependent (92). In endothelial cell cultures, cyclic strain has been shown to induce transcription factors that would bind to the MT1-MMP promoter and in turn cause increased MT1-MMP mRNA and protein levels (515, 533). In other studies, it has been demonstrated that cyclic strain can cause an induction of MMP-2 in both endothelial and vascular smooth muscle preparations (305, 475). However, the relative degree of MMP induction is likely to be time and stimulus-type dependent. For example, a small uniform biaxial strain reduced MMP-1 expression in human vascular smooth muscle cells (519). Whereas in another study, MMP-1 levels have been reported to be increased with cyclic stretching in human vascular smooth muscle cells (107). In other studies, relative MMP-2 levels were demonstrated to be altered as a function of the magnitude of cyclic strain and the duration of the strain (475, 519). In a study by Garcia and colleagues (332), it was demonstrated that local alterations in myocardial strain in vivo could alter local MMP levels. Specifically, in an intact canine preparation, local alterations in lengthening patterns by high rate pacing (i.e., changing the strain patterns) was associated with a robust increase in relative MMP-9 levels (Fig. 7). However, in this study, local oxidative stress and inflammatory markers were also increased within the region with abnormal strain patterns, and therefore, whether and to what degree the increased MMP-9 is from local synthesis or margination of inflammatory cells with a preformed reservoir of MMP-9 remains to be determined. Nevertheless, this in vivo study demonstrated an important relationship between changes in local myocardial deformation patterns to MMP induction.

View larger version (35K): [in this window] [in a new window]   FIG. 7. In a canine model of rapid pacing of the LV (LVP) in which the stimulation was confined to a focal region of the myocardium, increased total amounts of MMP-9 were observed as evidenced by proteolytic bands appearing by zymography (92/86 kDa). A: the proteolytic bands for MMP-9 were only increased in the LVP site, whereas there was no change in the LV remote (LVR) or right ventricle (RV). B: quantification of the MMP-9 proteolytic bands revealed that focal LVP increased both the latent and active forms. Thus a stimulus which caused a heterogeneous myocardial deformation caused an induction of MMPs, likely due to local changes in stress/strain patterns. [From Garcia et al. (123).]

The intent of this section was to provide a brief review on prototypical signals that would potentially cause transcriptional induction of MMPs. However, it must be recognized that all of these signals are not operative in a consistent fashion and are likely differentially induced depending on the cardiac disease state. Thus significant generalizations have been taken into how these biological stimuli can alter MMP transcription. Furthermore, it must be recognized that these pathways do not work in isolation but rather in a dynamic state within the myocardial interstitium. For example, mechanical stimuli can give rise to bioactive molecules and cause oxidative stress, which in turn cause MMP induction. For example, mechanical stretch increased MMP-2 mRNA levels, which was dependent, at least in part, on a ROS signaling cascade. Thus it is likely that simultaneous signals give rise to a multitude of transduction pathways and transcription factors that are integrated and eventually drive MMP transcription (Fig. 8) (142). Whether and to what degree one, several, or all of these pathways play a dominant role in MMP induction is likely dependent on the specific disease state such as MI, POH, or DCM. Indeed, as discussed in the sections which address each of these myocardial remodeling processes, a unique portfolio of MMPs is expressed within the myocardium that is likely due in large part to a specific set of operative biological/mechanical signals and ultimately differential MMP transcriptional processing.

View larger version (87K): [in this window] [in a new window]   FIG. 8. An important regulatory point of myocardial MMP abundance is transcriptional activity. A number of transcriptional binding elements such as AP-1, Ets, Sp1, and others exist on the promoter region of MMPs (Fig. 5). The formation of transcription factors in myocardial cells includes extracellular stimuli by bioactive molecules and cytokines and by mechanical signals. However, there are also factors on the promoter region that can potentially repress MMP transcriptional activity, and these include growth factors and subsequent activation and binding of SMAD proteins. [Adapted from Thomas et al. (444).]

The most important step regarding posttranslational modification is through the proteolytic activation of the proform of MMP to the active form, which has been discussed in a previous section. In addition to the classical means of pro-MMP activation, posttranslational modification of pro-MMPs by oxidative stress can also yield an active enzyme (116, 117, 143, 242, 481, 529, 540). For example, it has been demonstrated that a byproduct of oxidative stress, myeloperoxidase, can cause a transformational change within the MMP catalytic domain, yielding an active enzyme (116, 117). With the use of an isolated heart preparation, it was demonstrated that peroxynitrite could induce the release and activation of MMP-2 within the coronary circulation (481). Thus the effects of oxidative stress on myocardial MMPs are twofold. First, the formation of ROS causes a de novo increase in MMP transcription. Second, oxidative stress causes a posttranslational modification and activation of existing MMP reservoirs.

Since the MT-MMPs, such as MT1-MMP, are proteolytically active once inserted into the cell membrane, then posttranslational events are critical for yielding a fully functional enzyme. MT1-MMP contains an extracellular catalytic domain, a transmembrane domain, and an intracellular domain, all of which are critical for full functioning of the protease and modifications of these domains will alter MT1-MMP trafficking or activity (317, 327, 351–353, 413). It has been demonstrated that trans-Golgi processing and intracellular activational steps such as those by the intracellular protease furin play a critical role in processing the mature, full-length MT1-MMP (317, 353). Using an interstitial microdialysis technique, investigators in this laboratory have identified that MT1-MMP activity is increased following ischemia and reperfusion, which was associated with increased trafficking to the cell membrane (91). In a study by Remacle et al. (352), it was demonstrated that posttranslational modification of MT1-MMP, specifically O-glycosylation, altered MT1-MMP protein stability through a reduction in autocatalysis. In another study by this group of investigators, it was demonstrated that MT1-MMP could be internalized from the cell surface by both clatherin and clatherin-independent pathways, thus providing a pool of recruitable MT1-MMP (413). Thus a number of posttranslational events can alter the stability and turnover of MT1-MMP, which in turn would significantly alter activity. Since MT1-MMP is highly expressed within the remodeling myocardium in the context of MI and DCM (406, 503), then elucidating the regulatory mechanisms of posttranslational processing for MT1-MMP may yield new pharmacological targets.

E. The TIMPs

Active MMPs can undergo autodigestion and thereby lose proteolytic activity. However, the kinetics of this process are not fully understood and can be variable for different MMPs and conditions. A more critical control point for MMP activity is through the inhibition of the activated enzyme by the action of a group of specific MMP inhibitors termed TIMPs. There are four known TIMP species of which TIMP-1 and TIMP-2 have been the most studied. The TIMPs are low-molecular-weight proteins (190 amino acids) that can complex noncovalently with high efficiency to active MMPs in a 1:1 molar ratio (40, 58, 73, 90, 130, 133, 293, 420, 507). In general terms, TIMPs bind to the catalytic domain of active MMPs and thereby prevent access to substrates. The affinity of TIMPs to the active MMP site is quite high with a K_d of 10^–9 M (40, 58, 90, 507). While the relative binding affinity of TIMPs to different active MMPs can be dependent on assay conditions, it appears that TIMP-1 binds with less efficiency to MT-MMPs (40). TIMP-3 is unique among the known four TIMPs in that it binds directly to extracellular matrix proteins, and thereby can provide a means for stabilizing MMP-TIMP complexes within the interstitial space (328, 520). The binding of TIMP-3 to matrix proteins would also require close proximity of the active MMP site for effective inhibitory binding effects. TIMP-3 has also been demonstrated to inhibit a disintegrin and metalloproteinase (ADAM), notably ADAM-17, or most commonly termed TNF convertase (TACE) (6, 385). While the biological roles of TIMPs are likely to be diverse as discussed below, these small-molecular-weight proteins comprise an important endogenous system for regulating MMP activity in vivo. As a consequence, TIMPs, which are expressed in high abundance or with relative specificity to the myocardium, would directly affect MMP activity and subsequently the matrix remodeling process.

TIMP-4 is the most recently identified member of the TIMP family, in which a high degree of expression occurs within the cardiovascular system, most notably the myocardium (27, 136, 243, 311, 416). TIMP-4 was first identified in 1996 through sequencing a human heart cDNA library and maps to the human 3p25 chromosome (243, 311). This study and others demonstrated a very robust signal for TIMP-4 mRNA within the myocardium, but not in other organ systems (27, 136, 243). As with other TIMPs, TIMP-4 is a low-molecular-weight protein of 23 kDa and binds to active MMPs in the expected MMP-TIMP kinetics (27, 243). However, the amino acid sequence is significantly different from other TIMPs, and therefore, selective antisera to TIMP-4 have been developed (243, 422). As will be discussed in a subsequent section, changes in TIMP-4 levels may hold significance with respect to myocardial matrix remodeling from both a diagnostic and prognostic perspective.

As with MMPs, there are a number of transcription factor binding elements found within the promoter region of the TIMPs, which include AP-1, PEA-3, Sp1, and Ets (68, 470). At first, this would seem to imply that an extracellular stimulus would cause a concordant increase in both MMP and TIMP transcriptional activity, and under normal circumstances, this may be the case. However, there are distinct differences within the promoter sequences between MMPs and TIMPs, and between individual TIMPs, that provide for unique regulation and expression. For example, TIMP-2 contains a cluster of Sp1 and AP-2 motifs as well as a TATA-like element (86). Furthermore, exposure to phorbol esters, which in time would increase protein kinase C activity, increased TIMP-1 transcriptional activity, but TIMP-2 expression remained unchanged from basal levels (86, 151). TIMP-3 appears to be devoid of a TATA sequence, but contains multiple Sp1 sites (10, 498). In murine fibroblast systems, exposure to the steroid dexamethasone actually induced TIMP-3 expression, whereas TIMP-1 levels were suppressed (216). TIMP-3 also appears to have a restricted pattern of expression with high levels found in kidney, lung, and brain, which may be reflective of the unique transcriptional regulation of this TIMP (9, 216). Finally, murine TIMP-4 has a GATA binding site and a unique initiator-like element (136). One of the more interesting aspects of TIMP transcriptional regulation and the discordance with MMP transcriptional activity is with TGF (147, 150, 152, 219, 527, 531). For example, in a mesangial cell preparation, exposure to TGF reduced MMP-2 transcription but increased TIMP-1 (527). Thus increased levels of TGF, particularly on a chronic basis, would cause a reduction in MMP levels, heightened TIMP levels, and in turn favor matrix accumulation. However, it has also been demonstrated that initial exposure of TGF can cause an induction of MMPs, such as MMP-9 (152, 219). Thus it is likely that the effects of TGF on MMP/TIMP transcriptional activity are concentration, time, and tissue type dependent. While the regulation of TIMP expression is highly complex, the different combinations of cis-binding elements as well as the interaction of trans-activating factors located on the TIMP promoter can provide a regional and temporal regulatory mechanism for TIMP expression.

While a predominant characteristic of the TIMPs are in the inhibition of active enzymes, this is likely to be an oversimplistic view of the function of these proteins. In early biochemistry studies in which the relative affinity for TIMP binding to active MMPs was under investigation, it was noted that TIMPs may actually bind to the pro-MMP molecule (53, 203, 204, 419). Furthermore, this TIMP binding domain was distal from the MMP catalytic domain. There is now conclusive evidence that TIMPs bind to specific domains on inactive pro-MMPs (291, 507). One of the most studied with respect to this interaction is that of TIMP-2 binding to pro-MMP-2 (204, 291, 542). In this instance, a pro-MMP-2-TIMP-2 complex is formed which in turn can bind to a MT1-MMP dimer complex. This in turn causes the formation of a tetrameric structure that ultimately leads to proteolytic processing and activation of the bound MMP-2 molecule (291). However, an excess of TIMPs such as TIMP-2 can bind to MT1-MMP and thereby interrupt this process of activation. It also appears that TIMP-4 can bind to pro-MMP-2, but whether this can yield an activational complex with MT1-MMP remains unknown (26). In addition, studies have demonstrated that TIMPs exhibit growth factor-like properties and participate in apoptosis (32, 73, 145, 248, 307, 451). For example, TIMP-1 can suppress programmed cell death in a number of cell culture systems through the induction of antiapoptotic genes (32, 144, 145, 307). TIMP-1 and TIMP-2 can induce cell growth in a number of cell types including fibroblasts, whereas TIMP-4 may actually suppress cell growth (24, 248, 451, 517). These antiapoptotic/growth properties of TIMPs appear to be independent of any direct MMP inhibitory effects and therefore suggest the presence of a TIMP/receptor interaction (144, 145, 248). Indeed, initial radioligand binding assays provided evidence to suggest that TIMP-1 may signal through a cell surface receptor (24, 73). A clear demonstration of the differential effects of TIMPs on myocardial fibroblast growth and synthesis was performed by Lovelock et al. (248), and representative results are shown in Figure 9. In this study, transfection of TIMP-1, -2, -3, and -4 was performed by adenoviral constructs, and biological outcomes such as apoptosis rates, proliferation, and phenotypic differentiation were determined. While all TIMPs appeared to stimulate phenotypic differentiation into a myofibroblast phenotype, TIMP-3 only caused increased apoptosis, whereas TIMP-2 induced a robust increase in collagen synthesis rates. Thus TIMPs very likely have pleotropic effects relevant to myocardial matrix remodeling, many of which are likely to be independent of direct MMP inhibition.

View larger version (12K): [in this window] [in a new window]   FIG. 9. Overexpression of TIMP-1, -2, -3, and -4 was induced in murine myocardial fibroblasts by adenoviral-mediated transduction. A number of biological effects were observed by TIMP induction, which included effects on collagen synthesis (top) and apoptosis (bottom). These effects were not due to MMP inhibition, since pharmacological MMP inhibition did not recapitulate these effects, thus indicating a direct action of TIMPs on fibroblast function. Moreover, TIMP specific effects were observed where TIMP-2 caused a robust increase in collagen synthesis, whereas TIMP-3 accelerated fibroblast apoptosis. [Data from Lovelock et al. (248).]

	IV. MYOCARDIAL MATRIX METALLOPROTEINASES IN CARDIAC DISEASE

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The initial studies that identified that MMPs exist within human myocardium were initially performed using zymographic techniques and myocardial specimens obtained at cardiac transplantation (146, 456). With the use of a gelatin-impregnated electrophoretic platform, these initial studies as well as those that quickly followed (15, 229, 370, 444) demonstrated the presence of the gelatinases MMP-2 and MMP-9 within normal human myocardial specimens. With the use of immunochemical and gene expression approaches, the presence of MMPs within the normal adult human myocardium were identified that spanned all of the general classes of MMPs, and these studies formed the basis for presenting these specific MMP types in Table 1 (15, 158, 206, 229, 230, 370, 406, 444). For example, these studies demonstrated the presence of the interstitial collagenases MMP-1, -13, and -8. While it would be anticipated that MMP-1 would be present within the human myocardium as it is a ubiquitously expressed MMP, the initial discovery that MMP-13 was present, which was initially considered to be only highly expressed in rodent tissue and in malignant carcinomas, began the realization that a large portfolio of MMPs exist within the normal human myocardium. The presence of MMP-8, which was initially considered to be only expressed in peripheral inflammatory cells, demonstrated that endogenous cell types such as mast cells likely provide a source of local myocardial MMP-8 (1, 157, 403). The stromelysins, which include MMP-3, and the membrane-bound MMPs, which include MT1-MMP, were clearly identified within the human myocardium and thereby provided evidence that a localized proteolytic pathway existed for pro-MMP activation (406, 444). With the use of an immunohistochemical approach as well as a quantitative immunochemical approach, it has been demonstrated that MMP distribution may be chamber specific (158, 206, 285). For example, the relative levels of certain MMPs, such as MMP-1, appear lower in the right ventricle compared with the left ventricle (158, 206). While it remains to be established, it is likely that these differences in chamber specific MMP profiles are due to a combination of factors that include inherent differences in loading conditions, embryological origin, and cellular response to biological stimuli. With respect to TIMPs, all four TIMPs have been identified within the normal human myocardium (15, 158, 206, 230, 285, 406, 444). A robust signal for the cardiovascular-specific TIMP, TIMP-4, has been demonstrated in all four chambers of the human heart (229, 285, 444). Thus a full complement of MMPs and TIMPs exists within the normal adult human myocardium, and therefore, changes in the abundance and relative ratios of these proteolytic enzymes and inhibitors would likely contribute to changes in the myocardial matrix, which in turn would affect overall geometry and function. Indeed, direct relationships between changes in MMP and TIMP levels to overall changes in myocardial performance have been demonstrated within the human myocardium (206, 230).

B. MMPs in Myocardial Infarction

1. Human-based studies

Myocardial measurements of MMPs and TIMPs in the clinical context of MI and/or ischemia-reperfusion can be quite problematic. Nevertheless, an early post mortem study of patient samples following a significant MI was performed by zymography (453). In this study, increased lytic bands were noted on the zymographic electrophoretic gels in myocardial extracts taken from the MI region, reflective of increased MMP-2 and MMP-9 levels. In patients undergoing emergent cardiac surgery for an MI, it was demonstrated that increased zymographic levels of MMP-2 and MMP-9 occurred within the pericardial fluid (189). In another cardiac surgery study, right atrial biopsies were collected before myocardial arrest and cardiopulmonary bypass and at myocardial reperfusion (215). Increased zymographic levels of MMP-2 and in particular MMP-9 were observed in atrial myocardial samples following this brief period of ischemia-reperfusion. These investigators reported a relative reduction in TIMP-1 within the reperfused atrial myocardial samples. Finally, this clinical study demonstrated a net increase in relative MMP-2 and MMP-9 zymographic levels in plasma samples obtained directly from the coronary sinus. In the same clinical context of brief ischemia-reperfusion secondary to cardiac surgery, a past study by this laboratory demonstrated an absolute increase in pro-MMP-2 release across the myocardial circulatory bed using a quantitative immunoassay approach (181). As shown in Figure 10, a greater increase in pro-MMP-2 was released from the coronary sinus than that entering the coronary arteries indicative of de novo myocardial synthesis and release of pro-MMP-2. In a study utilizing circulating monocytes, it was demonstrated that an upregulation of EMMPRIN occurred in patients with acute coronary syndromes and was associated with increased levels of MT1-MMP (386). Thus, while the majority of these past studies in the clinical context of myocardial ischemia/infarction are indirect, it provides evidence that significant upregulation and expression of a large portfolio of myocardial MMPs occurs.

View larger version (6K): [in this window] [in a new window]   FIG. 10. Ascending aortic and coronary sinus plasma samples were collected in patients (n = 28) before and after elective coronary revascularization procedures requiring cardioplegic arrest and cardiopulmonary bypass (CPB). With the use of an enzyme-linked immunoassay (ELISA), quantitation of pro-MMP-2 levels was performed, and relative myocardial uptake or release was computed as the coronary sinus-aortic gradient. Prior to a brief period of ischemia-reperfusion, a slightly negative pro-MMP-2 gradient was observed, indicating a relative uptake of this pro-MMP within the myocardial circulation. In marked contrast, reperfusion reversed this gradient indicative of myocardial de novo synthesis and release of pro-MMP-2 (**P < 0.05 vs. pre-CPB values). [Data from Joffs et al. (181).]

Due to the inherent limitations of patient-based studies regarding MMP/TIMP myocardial levels, a large number of studies have been performed in animal models of MI. These past studies have performed a vast array of MMP/TIMP measurements within the myocardium using rodent as well as large-animal models of MI (13, 31, 81, 98, 103, 120, 138, 161, 179, 237–239, 263, 283, 286, 334, 338, 344, 361, 380, 423, 425, 469, 503, 525).

A) RODENT MODELS OF MI.  Inherent limitations exist for the study of matrix remodeling and MI in rodent models. These limitations include a relatively low myocardial collagen content compared with large animals and humans (2, 36, 182, 270, 474, 484, 488, 497), the intrinsic size of the LV which results in an extensive infarction of the LV free wall secondary to ligation of a major coronary vessel, and as discussed previously a different MMP portfolio than large animals and humans. These limitations not withstanding, some of the very studies that identified critical aspects of myocardial remodeling in the post-MI setting were made in rodent models (7, 76, 310, 335, 494). Moreover, the ability to develop transgenic constructs in murine systems and the organism size allows for unique drug interventions and thereby makes the rodent model one that allows for basic hypothesis testing and proof of concept studies (81, 98, 103, 120, 138, 161, 179, 237–239, 263, 286, 344, 361, 380, 423, 425). Clear examples of these transgenic/pharmacological approaches are provided in a subsequent section. In the murine model of MI, significant inflammation has been observed within the myocardium, which is accompanied by increased levels of MMP-2 and MMP-9 at both the mRNA and protein levels (98, 161, 263, 344, 425). In the majority of these studies, the emergence of MMP-9 was highest within the myocardium at 3–7 days post-MI, likely reflective of the acute inflammatory process (98, 344, 425). In this murine system of coronary ligation, Heymans et al. (161) reported increased MMP-9 levels within 7 days, which was followed by an increase in zymographic levels of MMP-2. TIMP-1 levels appear to be temporally delayed in expression in the post-MI murine myocardium (344), and this was most pronounced in male mice versus female mice. Overall, the emergence of the gelatinases MMP-2 and MMP-9 accompanied by the relative reduction in TIMP-1 would provide for an enhanced matrix proteolytic state, and as such, increased degradation of matrix components such as laminin have been reported (263).

In the rat model of MI, a robust and early increase in myocardial levels for the gelatinases MMP-2 and MMP-9 have been reported (138, 334, 425, 442). Using an MMP-2/-9 specific fluorogenic substrate, Villarreal et al. (469) demonstrated significant myocardial proteolytic activity as early as 2 h following coronary ligation (469). In a global ischemic isolated rat heart model, increased MMP-2 release was detected in the coronary effluent with reperfusion (72). In one of the more comprehensive time course studies performed in the rat MI model, Peterson et al. (334) demonstrated a robust increase in MMP-2 mRNA and protein levels by 24 h after coronary occlusion. Moreover, this past study demonstrated that a unique MMP signature occurred over time in the rat post-MI myocardium. As shown in Figure 11, the interstitial collagenase MMP-13 increased at 24–48 h post-MI and was then followed by a second peak at 2 wk post-MI. However, myocardial TIMP-1 mRNA and protein levels did not follow a similar temporal pattern. As a result, the relative MMP/TIMP ratio increased in the post-MI period, which would likely yield prolonged/persistent matrix proteolytic state. Indeed, this study as well as others demonstrated that this period of abnormal MMP/TIMP balance was associated with the greatest degree of LV remodeling as defined as LV dilation (334, 426, 442, 469).

View larger version (38K): [in this window] [in a new window]   FIG. 11. Time course of changes in both the mRNA and protein level for the interstitial collagenase MMP-13 (top) and for TIMP-1 (bottom) following MI induction in the adult rat. A biphasic peak in MMP-13, the predominant interstitial collagenase in the rat myocardium, at 7 and 14 days post-MI. While an early and brief peak occurred in relative TIMP-1 myocardial levels post-MI, relative levels fell over time, resulting in an imbalance in the MMP-13/TIMP-1 ratio that would favor an enhanced matrix proteolytic state (*P < 0.05 vs. relative sham controls). [From Peterson et al. (334).]

View larger version (58K): [in this window] [in a new window]   FIG. 12. Quantitative immunoblotting results of LV myocardial extracts taken at 2 mo post-MI in a sheep model. The results were normalized to reference normal controls, and values were distributed on a regional basis based on myocardial function and perfusion scores. The remote regions were the normally perfused sections most distal to the MI region, and the transition regions were those defined by abnormalities in myocardial function and perfusion moving closer to the MI region. Significant regional heterogeneity in MMP/TIMP profiles was observed post-MI. Specifically, the interstitial collagenases MMP-8 and -13 were increased within the transition and MI regions, but MMP-1 was not detectable. A robust increase in MMP-2 levels was observed within the transition and MI regions, but not MMP-9. The relative levels of MMP-3 remained constant in all regions, whereas MMP-7 levels fell significantly in the MI region. MT1-MMP, or MMP-14, increased significantly in the transition and MI regions. While a number of MMPs increased in the transition and MI regions, all four of the TIMPs fell significantly. Thus an imbalance between relative MMP/TIMP levels occurred within the remodeling myocardium post-MI. [From Wilson et al. (503).]

The changes within the myocardial matrix with POH or VOH were briefly reviewed in a previous section. Since these are distinctly different forms of overload, then there are distinct differences in the patterns of matrix remodeling, and in turn, differential MMP/TIMP profiles have also been identified.

1. Human-based studies

In human subjects with POH secondary to aortic stenosis, several studies have examined relative myocardial MMP and TIMP levels (108, 340). Fielitz et al. (108) demonstrated that relative MMP-1 and MMP-9 mRNA levels were reduced, whereas TIMP-2 and TIMP-3 levels were significantly increased in patients with severe POH compared with normal reference control preparations. Heymans et al. (162) reported that TIMP-1 and TIMP-2 levels were increased by twofold in patients with severe aortic stenosis and were most pronounced in those patients with severe POH. In a study by Polyakova et al. (340), increased relative MMP-1, -13, and -14 levels occurred in POH patients with a significantly depressed LV ejection fraction. While these clinical studies can only provide associative data, these results do imply that with POH in the human myocardium, an increase in relative TIMP levels occurs during the compensated state (LV function within normal limits), but that with decreased LV function, increased MMP levels begin to emerge. This relative change in MMP/TIMP levels would favor matrix accumulation and fibrosis early in the progression of POH, and matrix degradation and a loss of matrix structure in the later periods of POH. Indeed, in the study by Polyakova et al. (340), the relative degree of fibrosis appeared to parallel the changes in MMP/TIMP levels in patients with severe POH. To date, there have been no studies examining the relative changes in myocardial MMP/TIMPs in human subjects with VOH, such as that with mitral regurgitation.

2. Animal models

With the use of an aortic constriction model in mice, it has been demonstrated that relative levels of MMP-2 and TIMP-2 increased following 8 wk of POH and were associated with a transition to LV failure in mice (211). Gao et al. (122) demonstrated that removal of the aortic constriction in mice, following the development of POH, was associated with a normalization of MMP-2 levels and a persistently elevated myocardial collagen content. One of the more frequently studied rodent models of POH, and the relationship to MMP/TIMP levels, is the rat model of salt-sensitive hypertension or spontaneously developing hypertension and heart failure (157, 171, 176, 333, 358, 376). In general, these studies demonstrated increased levels of MMP-2 and MMP-9, which were associated with a transition from a stable POH state to one of decreased LV systolic performance. For example, as shown in Figure 13, a robust increase in relative MMP-9 and MMP-2 levels were observed in the spontaneously hypertensive heart failure rat compared with wild-type controls (333). Moreover, this increase in relative MMP levels was associated with the degree of LV systolic dysfunction. Thus, in these rodent models of POH, an early increase in relative TIMP levels occurs that is associated with an increase in matrix accumulation and eventually fibrosis. With a prolonged pressure overload stimulus, LV systolic dysfunction occurs and is associated with a robust increase in relative MMP levels. These observations would suggest that POH is not simply a factor of matrix accumulation, but a continuous process of matrix degradation and turnover, and the net balance of this process can affect both LV remodeling and function.

View larger version (19K): [in this window] [in a new window]   FIG. 13. Immunoblotting was performed on wild-type female (WF) and spontaneously hypertensive-heart failure female (SHHF) rat myocardial preparations for MMP-9 and MMP-2. A robust increase in relative MMP-9 and MMP-2 levels was observed in the SHHF rats at 9 and 13 mo. A robust increase in MMP-2 was observed in the SHHF rats at 13 mo and was associated with the progression to LV failure (#P < 0.05 vs. respective WF values). [Data from Peterson et al. (333).]

View larger version (14K): [in this window] [in a new window]   FIG. 14. Relative myocardial MMP-2 levels by zymography and mast cell density by histochemistry were temporally associated following the induction of an aortocaval fistula in rats. These findings suggest that the early increase in relative MMP levels following a volume overload stimulus may be due to endogenous cell sources, rather than an exogenous inflammatory infiltrate. Moreover, this early induction of MMP levels within the myocardium is associated with matrix remodeling and LV dilation. [From Brower et al. (46).]

View larger version (28K): [in this window] [in a new window]   FIG. 15. With the use of gelatin zymography, a robust proteolytic band corresponding to MMP-9 was observed following the induction of an acute (6 h) volume overload (A-VO) created by mitral regurgitation in dogs. This induction of MMP-9 did not persist with a prolonged pressure overload (P-VO) defined as 14 days following the induction of mitral regurgitation. *P < 0.05 vs. reference controls. [From Nagamoto et al. (294).]

Intrinsic cardiac muscle disease, which can be due to a wide variety of etiologies including infectious, metabolic, and genetic causes, has been generically termed as cardiomyopathic disease. One common cardiomyopathic disease state that is characterized by significant LV chamber dilation and severe systolic dysfunction is DCM. Since DCM is a progressive myocardial disease process that culminates in severe heart failure and hemodynamic collapse, then mechanical assist devices and/or heart transplantation are often required. As such, access to myocardial samples from DCM patients is possible and has allowed for an extensive survey of the MMP/TIMP system (15, 146, 158, 206, 229, 230, 285, 370, 406, 444, 456). In addition, several large-animal models have been utilized to examine changes in myocardial MMP/TIMPs during the progression of DCM. As a consequence, significant insight into the changes in the myocardial MMP/TIMP system and the relation to the LV remodeling process has been gleaned from these human and animal studies of DCM.

1. Human-based studies

One of the first comprehensive studies regarding differences in myocardial MMP levels in end-stage DCM was that of the Woessner laboratory (146). In this study, radioactive collagen isolated from rat skin was incubated with myocardial extracts from DCM and referent controls. This collagenase assay demonstrated a 30-fold increase in DCM myocardial extracts as shown in Figure 16. Moreover, this past study used gelatin zymography and demonstrated increased relative levels of both MMP-2 and MMP-9 within DCM extracts. Using specific antisera directed against MMPs, this laboratory demonstrated increased levels of MMP-2, -3, and -9 with DCM, but interestingly a significant decrease in MMP-1 (444). In a follow-up investigation, we reported that myocardial MT1-MMP and EMMPRIN were both significantly elevated in patients with DCM (406). Moreover, levels of certain MMPs, such as MMP-13, which are expressed at very low levels within the normal myocardium were significantly increased in DCM (406). These studies and others (15, 158, 206, 230, 285, 406, 444, 456) suggest that selective changes in myocardial MMP profiles occur that are likely due to transcriptional regulation. Moreover, there is an emergence of MMPs such as MMP-13 and MT1-MMP with DCM which contain a diverse portfolio of proteolytic substrates and therefore may significantly contribute to adverse LV remodeling. In a study by Rouet-Benzineb et al. (370), it was demonstrated that MMP-2 and -9 were increased in DCM and was identified that MMP-2 levels were actually increased not only within the myocardial interstitium, but also the cardiocyte. Moreover, these investigators as well as others provided evidence that MMP-2 may degrade contractile proteins such as myosin (379, 482). Thus increased MMP levels within the myocardium of patients with DCM may have multiple consequences that include matrix degradation and proteolytic activation of biologically active signaling molecules and, finally, directly affect myocyte structure and function.

View larger version (9K): [in this window] [in a new window]   FIG. 16. Myocardial extracts from reference controls and from patients with dilated cardiomyopathy were incubated with radioactive collagen prepared from rat skin. The amount of radioactivity released into the supernatant was reflective of collagenase activity. These assays were performed in the presence and absence of an organomercurial compound (aminophenylmercuric acetate) to determine active and total amounts of collagen-degrading enzymes. Total myocardial collagenase increased by over 30-fold with DCM, and a much higher proportion existed in the active state when compared with reference controls. [Data from Gunja-Smith et al. (146).]

View larger version (22K): [in this window] [in a new window]   FIG. 17. Immunoblotting results for TIMP-3 in myocardial samples taken from a nonfailing (NF) patient and from patients with either idiopathic dilated cardiomyopathy (DCM) or ischemic cardiomyopathy (ICM). As with all TIMPs, TIMP-3 is a low-molecular-weight protein as evidenced by the positive recombinant control band (+) at 20 kDa. A strong immunoreactive signal was observed in the NF myocardial sample at this low molecular weight as well as at higher molecular weights, likely reflecting TIMP-3 dimerization and binding to active MMPs. The immunoreactive signal for TIMP-3 was reduced in both DCM and ICM. [From Li et al. (229).]

View larger version (26K): [in this window] [in a new window]   FIG. 18. MMP zymography was performed on myocardial extracts from DCM patients with either ischemic (ICM) or idiopathic (DCM) etiologies at the time of ventricular assist device placement (A) and after an interval of ventricular assist support (B). The duration of ventricular support averaged 4 mo, and a robust reduction in relative MMP-9 levels was observed following ventricular support. [From Li et al. (230).]

Two animal models that reasonably recapitulate ischemic DCM and idiopathic DCM are the microembolization model and the rapid pacing model, respectively (202, 282, 347, 408). While there are inherent limitations in both of these model systems of DCM (526), these large-animal models allow for deriving relationships between the LV remodeling process and changes in relative myocardial MMPs. In the canine model of repetitive coronary microembolization, LV dilation and dysfunction occurs that is accompanied by increased levels of MMP-2, -3, and -13 (282, 347). In this model, multiple discrete areas of myocardial injury occur that are accompanied by degradation of the normal matrix and focal fibrosis. Moreover, both pharmacological and mechanical strategies that reduced the degree of LV dilation in this canine model of DCM were associated with a favorable directional change in myocardial MMP levels (282, 347). In the rapid-pacing pig model, a direct temporal relationship was observed between relative increases in certain myocardial MMP levels and LV remodeling (408, 526). As shown in Figure 19, a loss of normal myocardial matrix architecture occurred as a function of rapid-pacing duration. The loss of myocardial matrix structure was accompanied by a robust and early increase in relative MMP levels, as determined by zymography. The myocardial matrix dissolution and increased levels of MMPs were directly associated with the degree of LV dilation (408). Moreover, with pacing-induced DCM, the early changes in myocardial matrix structure and MMP levels actually preceded significant changes in myocyte contractile performance. Thus, in both of these models, the progression of DCM was directly accompanied by changes in the myocardial matrix and induction of MMPs.

View larger version (52K): [in this window] [in a new window]   FIG. 19. A: chronic rapid pacing in pigs over a 21-day period causes time-dependent changes in the LV myocardial matrix, which were readily observed by scanning electron microscopy. LV dilation occurs as early as 7 days of rapid pacing and is accompanied by a discrete area of collagen dissolution and disorganization. These areas of myocardial matrix disruption become more apparent by 14 days of pacing, and large areas of collagen loss were observed by 21 days of pacing (arrows). B: the temporal changes in the LV myocardial matrix that occurred with chronic rapid pacing were accompanied by a clear increase in myocardial MMP levels as measured by zymography. The most notable change was the increase in the 72-kDa and lower molecular weight proteolytic bands, most likely corresponding to MMP-2 at 7 and 14 days of pacing. + Control, cell extract from a fibrosarcoma cell line (HT1080). [From Spinale et al. (408).]

	V. MYOCARDIAL MATRIX METALLOPROTEINASES: LESSONS FROM TRANSGENICS/GENETICS

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View larger version (30K): [in this window] [in a new window]   FIG. 20. Summary of results from MMP/TIMP transgenic studies.

One of the particular MMP types with a diverse promoter region, and is induced in a variety of cardiac disease states, is the gelatinase MMP-9 (71, 118, 123, 152, 228, 235, 302, 308, 400, 401, 403, 511). Accordingly, it would follow that this specific MMP was the focus of targeted gene deletion in murine constructs (98, 161, 237). While this is a global deletion of MMP-9, these mice develop normally and appear to have a relatively benign phenotype in the absence of pathophysiological stress. However, as reported by Ducharme et al. (98), surgical MI induction in MMP-9 null mice resulted in a reduction in the degree of LV dilation and adverse matrix remodeling. Interestingly, these investigators reported a reduction in collagen accumulation within the MI region which was accompanied by a reduction in macrophage infiltration. These findings were confirmed in a study by Lindsey et al. (237) where it was demonstrated that macrophage infiltration was retarded in MMP-9 null mice post-MI, but moreover, a relative increase in vascularity and perfusion occurred in these transgenic mice. These observations suggest that MMP-9 is involved in inflammatory cell infiltration following myocardial injury, is likely involved in processing a number of signaling molecules which regulate vascular growth, and contributes to adverse LV remodeling post-MI. Indeed, Heymans et al. (161) reported that the incidence of cardiac rupture was greatly reduced in MMP-9 null mice following MI, further supporting the role of this MMP type in adverse myocardial remodeling. Targeted global gene deletion of MMP-2 has also been accomplished in mice (263, 265). In the MMP-2 null mouse, a reduction in the rupture rate following MI has been reported (263). In this study, a similar finding to that of the MMP-9 null mouse was observed in that the degree of adverse LV remodeling was attenuated and was accompanied by a reduction in macrophage infiltration into the MI region. In a murine model of POH induced by aortic constriction, the LV hypertrophic response was blunted in MMP-2 null mice (265). Thus gene deletion of either gelatinase MMP-9 or MMP-2 was associated with significant effects on myocardial matrix remodeling and, in turn, altered the course of LV myocardial remodeling. These findings supported a mechanistic role for both MMP-2 and -9 in adverse LV myocardial remodeling processes. Another important outcome from these studies was the demonstration that removal of a specific MMP type from the entire MMP portfolio was not associated with adverse consequences on the normal wound healing response and adaptation to myocardial injury. However, questions remain unanswered from these studies. First, it remains unclear whether gene deletion of both MMP-2 and -9 would provide an additive or synergistic effect on LV remodeling. Second, it is not clear whether gene deletion of MMP-2 or MMP-9 actually prevents or simply delays adverse LV remodeling following such as that with an MI or POH. Third, the actual specificity and thereby mechanism(s) which contribute to the specific beneficial effects of these targeted gene deletion studies remain unclear. Specifically, it remains to be established whether the effects of MMP-9 deletion are directly due to reduction in net matrix proteolytic activity, or rather through inhibition of a biological cascade of events such as inflammatory cell infiltration.

The consequences of gene deletion of stromelysin MMP-3, or matrilysin MMP-7, have been examined in murine models of myocardial injury (238, 284). In the MMP-3 null mice, abnormalities in the immune response have been demonstrated which included defects in cellular proliferation and cytokine release (479). As a result, these mice exhibit reduced contact hypersensitivity response following exposure to specific antigens. In keeping with this observation, it was demonstrated that scar maturation was impaired following a discrete radiofrequency-induced myocardial injury (287). Specifically, scar volumes were increased in MMP-3 null mice at 3 days following myocardial injury and were accompanied by reduced inflammatory cell infiltration. These findings would suggest that MMP-3 is important in mounting a normal injury response. In MMP-7 null mice, early post-MI survival was increased despite equivalent MI sizes (238). Moreover, myocardial conduction patterns, particularly along the viable border region of the MI, were improved in the MMP-7 null mice. This past study also provided evidence that a proteolytic substrate for MMP-7 was connexin-43 (238). These findings would suggest that the induction of MMP-7 in the early post-MI period may cause disruption of transmembrane/matrix proteins important in myocardial conduction. While inherent limitations exist with any transgenic construct, the findings from these MMP-3 and MMP-7 gene deletion studies demonstrated that unique roles and substrates likely exist for specific MMP types in the myocardial wound-healing response.

The global gene deletion of MT1-MMP demonstrates how certain MMP types are critical in development and normal growth regulation (18, 165). Specifically, MT1-MMP null mice demonstrate severe growth retardation, a failure of adequate bone formation, and severe connective tissue malformations (165). The loss of this membrane-bound MMP likely results in the failure of processing and activation of other MMPs, as well as focal matrix degradation, which in turn prevents the necessary matrix patterning for normal development (18). While not specific to the myocardium, these gene deletion studies demonstrated the essential and multifactorial functions that MT1-MMP likely plays in matrix remodeling processes.

B. Targeted Gene Deletion of TIMPs

Murine transgenic models have been successfully constructed with either TIMP-1 or TIMP-3 gene deletion (106, 173, 287, 369). In the TIMP-1 null mouse, no distinctive myocardial phenotype could be observed in the absence of a pathological stimulus. However, an accelerated LV dilation occurs following surgically induced MI, which is accompanied by worsened LV systolic performance (173, 287, 369). The architectural organization of the myocardial fibrillar collagen was altered in the TIMP-1 null mice and was accompanied by reduced collagen content within the remote zone post-MI (173, 287, 369). The effects of TIMP-1 gene deletion were likely due to loss of MMP inhibitory control, since pharmacological MMP inhibition instituted in the post-MI period yielded a myocardial phenotype similar to reference wild-type animals (173). In a discrete myocardial injury model, where significant LV dilation and dysfunction are absent, TIMP-1 null mice exhibited a greater degree of matrix remodeling within and around the site of injury (287). With respect to TIMP-3 gene deletion, a much more significant phenotype becomes manifest (106). Specifically, significant LV dilation and dysfunction occurs as a function of age in the TIMP-3 null mice, which is not apparent in wild-type, age-matched controls. As shown in Figure 21, significant LV dilation and wall thinning occurred in the TIMP-3 null mice as a function of age, which was not apparent in wild-type littermates. Moreover, the fibrillar collagen matrix was significantly disrupted with areas of collagen loss between myocytes. Moreover, this past study demonstrated that in TIMP-3 null mice, higher myocardial levels of TNF occurred, suggesting increased cytokine processing/activation (106). Using an in vitro fibroblast system, accelerated MMP-2 activation occurred in TIMP-3 null cells compared with TIMP-2 null fibroblasts (100). Taken together, the different myocardial phenotypes with TIMP-1 and TIMP-3 deletion and the observations from in vitro studies further emphasize the potential different functions that these TIMPs may play with respect to myocardial remodeling.

View larger version (66K): [in this window] [in a new window]   FIG. 21. Left: myocardial cross sections taken at autopsy of a wild-type LV and an LV from a TIMP-3 null mouse, both at 21 mo of age. Significant LV dilation and wall thinning could be observed in the TIMP-3 null myocardial section, consistent with a DCM phenotype. Right: photomicrographs of myocardial sections stained for the collagen matrix in a circumferential (top) and in a longitudinal (bottom) orientation. Significant disruption and dissolution of the collagen matrix could be observed in the TIMP-3 null mice. Bar for collagen micrographs is 10 µm. [Adapted from Fedak et al. (106).]

With the use of the -myosin heavy chain promoter, cardiac-restricted overexpression of MMP-1 and MMP-2 have been achieved in murine constructs (21, 201). Kim et al. (201) overexpressed human MMP-1 within the myocardium and demonstrated that by 12 mo of age, significant myocardial collagen disruption and LV dysfunction occurred. Since the predominant collagenase expressed within the murine myocardium is MMP-13, the expression of MMP-1 introduced an exogenous MMP type. While there are a number of limitations to this approach which include nonspecific interactions arising from overexpression of normally absent protein, this study provided mechanistic evidence that heightened MMP expression within the myocardium will result in LV remodeling and dysfunction. In a study by Bergman et al. (21), cardiac-restricted overexpression of MMP-2 caused marked LV remodeling and dysfunction. As shown in Figure 22, by 8 mo of age cardiac-restricted MMP-2 overexpression caused a phenotype consistent with DCM. In this study, the investigators carefully evaluated load-independent measures of LV function and demonstrated clear contractile defects in this MMP-2 transgenic line (21). However, the exact proteolytic pathways that are amplified by MMP-2 overexpression and are causative for progressive LV remodeling remain to be established. Nevertheless, these studies demonstrated that overexpression of MMP-2, which is ubiquitously expressed throughout the myocardium, causes matrix degradation and myocardial remodeling consistent with that observed in human forms of DCM.

View larger version (35K): [in this window] [in a new window]   FIG. 22. LV myocardial cross sections taken from a wild-type mouse and from a mouse with cardiac restricted overexpression of MMP-2 taken at 8 mo of age. Significant LV dilation and wall thinning were observed with overexpression of MMP-2. [From Bergman et al. (21).]

In other studies, the full-length promoter region for MMP-2 or MMP-9 fused to a reporter has been permanently ligated into the murine system (4, 220, 286). With the use of this approach, MMP transcriptional activity can be quantified as well as localized. For example, using the MMP-2 or MMP-9 reporter mice, the spatiotemporal transcriptional activity could be visualized within the intact heart following MI (286). As shown in Figure 23, MMP-9 transcriptional activation occurred within and around the MI region early following coronary ligation and was particularly prominent within the border region. MMP-2 transcriptional activation occurred within the MI region, and persistent activation into the remote, viable myocardium could be observed by 1 mo post-MI. In this study, activation of the MMP-9 promoter was colocalized to inflammatory cells, whereas MMP-2 promoter activation was localized to cell types consistent with a fibroblast phenotype (286). These reporter studies clearly demonstrated that a robust and prolonged increase in MMP transcriptional activity occurs following MI and extends into the viable, normally perfused myocardium.

View larger version (39K): [in this window] [in a new window]   FIG. 23. The full-length human MMP-2 or MMP-9 promoter was ligated to the -galactosidase reporter and fused into mice (4, 220, 286). This approach provides for spatial localization of MMP-2 and MMP-9 promoter activity. Coronary ligation was performed in these reporter constructs and reporter levels visualized at 1–28 days post-MI. MMP-2 promoter activity could be readily observed by 3 days post-MI and MMP-9 promoter activity by 7 days post-MI. MMP-2 promoter activity was localized to the MI region, and then with longer periods post-MI extended to the border and remote regions. Intense MMP-9 promoter activity could be observed within the area surrounding the MI (border region), which then extended into the remote regions with longer post-MI periods. Scale bar, 2 mm x 2 mm square. [From Mukherjee et al. (286).]

Clinical studies have now identified variant forms contained within the DNA sequences of MMP genes, or polymorphisms, for several of the MMP subtypes (25, 30, 65, 163, 240, 241, 258, 273, 277, 304, 329, 377, 440, 466, 514, 539). The polymorphisms that have been identified thus far often affect the promoter region of the MMP gene, and thereby influence critical steps in the binding of transcription factors or the overall efficiency of transcription. An overview of some of the major polymorphisms reported with respect to MMP-9, -2, -3, and -1 and the potential consequences of these alterations in DNA sequences are summarized in Figure 24.

View larger version (15K): [in this window] [in a new window]   FIG. 24. Polymorphisms in several MMP promoter sequences have been identified from clinical studies, and the more common variants are outlined on the left. These polymorphisms often entail a single base pair substitution within the promoter locations as indicated. The biological effects and any clinical associative data associated with these MMP promoter variants have been summarized. The references in which these data were extracted are shown.

A naturally occurring variant in the MMP-3 promoter region is the 5A and 6A alleles, which signify a 5 or 6 adenine sequence, respectively. The 5A allele has been associated with increased MMP-3 promoter activity, and in turn increased relative MMP-3 protein levels (273). In contrast, the 6A allele has been associated with reduced MMP-3 promoter activity. In patients homozygous for the 5A allele, a corresponding increased MMP-3 tissue levels occurred, whereas in patients homozygous for the 6A allele, decreased MMP-3 tissue levels were observed (273). In a study performed in over 2,800 Japanese patients, the 5A polymorphism was associated with increased risk of MI in women (514). Mizon-Gerad et al. (277) examined the potential relationship between the MMP-3 gene polymorphism and outcomes in patients presenting with preexisting LV failure, due to cardiomyopathy. In this study, over 400 patients were genotyped with respect to the MMP-3 polymorphism (5A/6A allele). These investigators observed that homozygosity for the 5A allele in patients with nonischemic cardiomyopathy was associated with poorer survival, and statistical modeling revealed that this MMP-3 polymorphism was an independent predictor of cardiac mortality with (hazard ratio of 2.92). However, the relationship between the MMP-3 polymorphism was not observed in patients with ischemic cardiomyopathy.

MMP-2 polymorphisms comprising a single substitution within the promoter region (–1306C/T or –790T/G) have been examined in clinical studies (277, 466). While these variants in the MMP-2 promoter may cause increased transcriptional activity, the relationship to adverse LV remodeling or cardiovascular events remains to be established. In patients with DCM, a relationship between the 1360C/T MMP-2 polymorphism and clinical aspects of disease progression could not be identified (277). In a preliminary clinical study, the addition of a guanine within the MMP-1 promoter region (–1607 1G/2G) was associated within an acceleration of adverse LV myocardial remodeling in patients post-MI (258). In another study, certain single nucleotide polymorphisms within the MMP-1 promoter that may actually reduce MMP-1 transcriptional activity were identified and associated with reduced risk of MI (329). As this area of research continues, it is very likely that variants within the promoter region that affect transcriptional activity for all MMP types will be identified.

While the studies outlined above examined the potential relationship between specific MMP gene polymorphisms and clinical outcomes in patients with LV remodeling and failure, it must be recognized that these MMP genotyping studies do not provide a clear cause-effect relationship between the MMP system and cardiac mortality. Another consideration is that these MMP polymorphisms may not occur as independent events but rather be associated with other polymorphisms in the genome, such as cytokines and mediators of the inflammatory response. However, it is intriguing to speculate that these MMP polymorphisms may identify those patients that may be more vulnerable to adverse myocardial remodeling and therefore a more rapid progression of the heart failure process.

	VI. MYOCARDIAL MATRIX METALLOPROTEINASES: LESSONS FROM PHARMACOLOGY

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Due to the fact that MMPs play a prominent role in tissue remodeling processes, a large effort was put in place to develop pharmacological MMP inhibitors (83, 93, 99, 172, 267, 319, 320, 332, 354, 357, 363, 445, 528). The development efforts were not targeted toward myocardial remodeling per se, but rather for indications in cancer and rheumatologic/inflammatory disorders. Excellent and extensive reviews on the pharmacological development of these compounds which caused inhibition of active MMPs have been provided elsewhere (83, 267, 319, 320, 332). Certain aspects of the pharmacological development of these MMP inhibitors hold special bearing with respect to myocardial remodeling and will be examined in some detail. The first generation MMP inhibitors to be developed for clinical indications were hydroxymate based, such as marimastat (354, 363, 445). Initially, these compounds were developed to treat connective tissue disorders such as arthritis, but were clinically evaluated in the context of severe gastrointestinal cancers such as pancreatic cancer (363, 445). In these studies, a significant and somewhat paradoxical systemic side effect was reported that was termed the musculoskeletal syndrome (MSS) or the "frozen joint" syndrome (320, 332, 354, 363, 445, 528). Specifically, in the case of marimastat, patients appeared free of symptoms for the first month of treatment, but MSS began to be reported in 30% of patients subsequently treated for 2–6 mo (445). Eventually, the symptoms of MSS became so severe that the dose of marimastat was reduced in 15% of the patients enrolled in the study. In another study performed in cancer patients, symptoms consistent with MSS were reported (363). While the mechanistic basis for MSS remains poorly understood, the use of hydroxymate-based MMP inhibitors was abandoned. Accordingly, a number of nonhydroxymate MMP inhibitors were developed, and the structure and inhibitory profiles have been reviewed previously (267, 319, 332). One of the first of these compounds to emerge with potential indications in cardiovascular disease was the MMP inhibitor PD167793, developed by the former pharmaceutical company Parke-Davis (60, 283, 332, 333, 407, 524). The structure of this particular MMP inhibitor is shown in Figure 25. This particular MMP inhibitor exhibited an inhibitory effect on a wide range of MMPs within the nanomolar concentration range, without any inhibitory effects on other metalloproteases such as angiotensin converting enzyme (ACE) (333). Since these MMP inhibitors exhibited inhibitory effects across a wide range of MMP types, these compounds were generically termed "broad-spectrum" MMP inhibitors. As detailed below, preclinical studies of these broad-spectrum MMP inhibitors were successfully performed in several animal models of LV remodeling. However, it remained unclear whether and to what degree these broad-spectrum MMP inhibitors may affect closely related proteases such as the ADAMs (a disintegrin and metalloprotease). Moreover, it was postulated that the inhibition of certain MMPs, such as MMP-1, may significantly contribute to the development of MSS (319, 332). Accordingly, more selective MMP inhibitors were developed that could be pharmacologically titrated to avoid inhibition of certain MMP types, particularly MMP-1. The most clinically advanced of these "selective" MMP inhibitors in terms of cardiovascular disease was PG11680 (also referred to as PGE530742/PGE7113313) (8, 202, 239, 282). This compound was considered MMP selective due to the fact that this compound could effectively inhibit certain MMP types such as MMP-13, -2, -8, -9 at concentrations of 20 ng/ml, but would not effectively inhibit MMP-1 or MMP-7 until concentrations of >1 mg/ml (8, 44, 168, 202). This selective MMP inhibitor was evaluated in several animal models of myocardial remodeling and eventually advanced to a clinical study. These pharmacological developments and studies are likely to be considered the first iteration of selective MMP inhibitors, as compounds with a much more restricted inhibitor profile are under development (83, 93, 99, 172, 357). Finally, it must be recognized that therapeutic interventions such as agents that inhibit neurohormonal activity or mechanical stimuli would likely in turn modify MMP expression/activity (31, 171, 193, 211, 227, 338, 344, 376, 380, 425). Accordingly, prototypical examples of these interventions are also briefly summarized in the following section.

View larger version (4K): [in this window] [in a new window]   FIG. 25. Structure of the broad-spectrum, orally bioavailable MMP inhibitor PD-166793. This compound was developed by Parke-Davis and evaluated in a number of preclinical studies of myocardial remodeling. The structure of this inhibitor is such that it binds to the active domain of all MMP types with a high (nanomolar) inhibitory potency and therefore is designated as a broad-spectrum MMP inhibitor. [From Peterson (332).]

In a coronary ligation mouse model, Rohde et al. (361) demonstrated that broad-spectrum MMP inhibition reduced the degree of LV dilation post-MI (361). The MMP inhibitor was administered by oral gavage and end-point studies were performed at 4 days post-MI. LV echocardiography was performed at baseline, prior to MI induction, and at 4 days post-MI. The results from this study are summarized in Figure 26. A significant increase in LV end-diastolic dimension occurred in the untreated (placebo) mice at 4 days post-MI, which was attenuated by MMP inhibition. LV systolic function, as measured by fractional shortening, was reduced in untreated mice post-MI. This decline in LV fractional shortening was attenuated in the mice treated with the broad-spectrum MMP inhibitor. Using a rat MI model, Villarreal et al. (469) demonstrated that doxycycline, which possesses broad-spectrum MMP inhibitory activity, reduced the degree of adverse LV remodeling as defined by shifts in the LV pressure-volume relationship. However, these rodent studies introduced MMP inhibition either before or early after MI induction, which may not be clinically applicable. Accordingly, additional studies have utilized a large-animal MI model in which MMP inhibition was not instituted until 5 days post-MI (283, 524). There are several reasons for employing this type of experimental design. First, the initial myocardial injury is associated with an acute inflammatory response and the release of degradative enzymes that facilitate wound healing (43, 303, 491). Second, inhibition of this early wound healing response may adversely alter the myocardial matrix (205, 473). Third, development of an MMP inhibition strategy that could be implemented after initial interventional strategies would hold clinical relevance. In one such study, broad-spectrum MMP inhibition was initiated at 5 days post-MI in pigs, and regional MI expansion was quantified for up to 2 mo post-MI (283). As shown in Figure 27, radio-opaque markers were placed within the MI region, and the size of this marker area and the rate of expansion were serially measured with and without MMP inhibition. This reduction in relative MI expansion with MMP inhibition was translated into an attenuation in LV dilation (283, 524). Moreover, these studies demonstrated an improvement in the composition and structure of the myocardial matrix post-MI, particularly that within the border zone with MMP inhibition. Finally, these studies uniformly reported that increased collagen accumulation, or increased fibrosis, did not occur within the myocardium with MMP inhibition. Taken together, these animal studies provided proof of principle that MMP activation contributed to adverse LV remodeling post-MI.

View larger version (9K): [in this window] [in a new window]   FIG. 26. Changes in echocardiographic indices of LV size and function following MI induction in mice treated without (placebo) and with a broad-spectrum MMP inhibitor. MMP inhibition was instituted 24 h after MI induction, and studies were performed at 4 days post-MI. The degree of LV dilation and systolic dysfunction were attenuated in the mice treated with the MMP inhibitor. [Figure generated using data reported by Rohde et al. (361).]

View larger version (58K): [in this window] [in a new window]   FIG. 27. Top: changes in regional myocardial geometry following induction of MI in pigs was performed using radio-opaque markers placed within the MI region. Bottom: at 5 days post-MI, broad-spectrum MMP inhibition or vehicle (MI only) was instituted, and regional MI size and rate of infarct expansion were quantified for up to 8 wk post-MI. Broad-spectrum MMP inhibition reduced the overall extent and rate of MI expansion. [From Mukherjee et al. (283).]

View larger version (14K): [in this window] [in a new window]   FIG. 28. An aortocaval fistula was induced in adult rats to induce LV volume overload. In one set of rats, broad-spectrum MMP inhibition was instituted (treated) after induction of the LV volume overload. The degree of LV remodeling was assessed at 8 wk using an ex vivo measurement of the LV pressure-volume relationship. Significant LV dilation indicative of increased LV volumes at an equivalent pressure was observed in the untreated LV volume overload rats which was attenuated with MMP inhibition. [From Chancey et al. (60).]

B. Selective MMP Inhibition Studies

While the broad-spectrum MMP inhibition studies provided a clear cause-effect relationship between MMP induction/activation and adverse LV myocardial remodeling, these compounds were not likely candidates to be advanced to clinical application. There were a number of reasons that precluded further clinical consideration of these compounds which included: 1) concern that any construct that provided broad-spectrum MMP inhibition would cause systemic side effects such as MSS, 2) not all MMPs are uniformly increased in LV remodeling processes such as post-MI (503), and 3) an accepted clinical approach to measure adequate MMP inhibition remained to be established. In light of these concerns, selective MMP inhibition strategies were evaluated in preclinical studies of LV remodeling (8, 202, 239, 525). As described in a previous section, one of these selective MMP inhibitors was PGE530742/PGE7113313. This MMP inhibitor underwent pharmacokinetic studies in the pig model and was utilized in studies of pacing-induced DCM and post-MI remodeling (8, 202, 525). As shown in Figure 29, this particular compound would inhibit MMP types such as MMP-1 and MMP-7 at only very high concentrations, and therefore, dosing could be titrated in such a manner as to avoid inhibiting these particular MMP types. This effectively MMP "sparing" inhibitor was demonstrated to effectively attenuate the degree of LV dilation in pigs with chronic rapid pacing (202). In the pig post-MI model, the degree of LV dilation was reduced with this selective MMP inhibitor, albeit to a slightly less degree than with broad-spectrum MMP inhibition (8, 525). This selective MMP inhibitor has also been examined in the canine model of ischemic DCM (282). In this study, DCM was induced by sequential coronary microembolizations and the animals then randomized to selective MMP inhibition. Following a 3 mo follow-up interval, LV volumes were lower and ejection fraction higher in DCM animals treated with selective MMP inhibition. There were several important outcomes from these studies. First, these studies further confirmed the underlying cause-effect relationship between MMP activation and adverse LV remodeling. More importantly, these studies demonstrated that the beneficial effect of MMP inhibition on LV remodeling was not due to a specific class of compounds. Second, these studies demonstrated that inhibiting the entire myocardial MMP portfolio was not necessary to alter the course of LV remodeling. Thus these studies provided the initial evidence that a restricted number of MMP types may contribute to adverse myocardial remodeling. Third, these studies provided the fundamental preclinical proof of concept studies to move forward with a clinical study.

View larger version (18K): [in this window] [in a new window]   FIG. 29. A single dose of the MMP inhibitor PGE530742 was orally administered to adult pigs, and blood samples were serially collected for plasma drug concentrations. The concentration of this MMP inhibitor necessary to achieve a 50% inhibitory effect (IC50) for certain MMP types is shown by the dashed lines. Plasma concentrations of this MMP inhibitor never approached those necessary for effective inhibition of MMP-1 or MMP-7. Based on this effect, this MMP inhibitor was termed an MMP-1/-7 sparing inhibitor, or selective MMP inhibitor. It should be noted that fairly rapid clearance of this drug occurred, and therefore, a three times daily dosing schedule was utilized in subsequent animal studies. Bottom: the in vitro inhibitory values for PGE530742 demonstrating the significant fold difference in IC50 for MMP-1/-7 as opposed to other MMP types. [From Yarbrough et al. (525).]

The selective MMP inhibitor described in the previous section (PGE530742/PGE7113313) was advanced to clinical evaluation and therefore was assigned a new identification number: PG116800 (44, 168). The target of this clinical evaluation was post-MI patients, and the study was entitled "Selective Matrix Metalloproteinase Inhibitor to Prevent Ventricular Remodeling After Myocardial Infarction (Prevention of Myocardial Infarction Early Remodeling; PREMIER)." The PREMIER study recruited 253 patients, primarily from international study centers that were diagnosed with an initial severe MI. Specifically, patients with an anterior-lateral MI causing ST segment elevation and an immediate and severe reduction in LV function as defined as an ejection fraction <40% were included. Patients were randomized to an active treatment arm consisting of selective MMP inhibition or placebo. Thus this study was conducted as a double-blind, prospective placebo-controlled trial. Treatment began within 48 h of presentation with an MI. Initially, the study design called for a 200-mg dose to be given orally twice daily for the entire study interval of 180 days. However, due to historical concerns regarding the risk of MSS and some additional data obtained in patients with osteoarthritis, the dosing regimen was altered following initial launch of the study (44, 168). Specifically, patients randomized to PG116800 were treated initially with 200 mg twice daily for the first 30 days and then 200 mg orally once per day for the remainder of the study period. The major end point of this study was echocardiographic indices of LV size and function. Over 80% of the patients recruited into this study were from Poland or Canada. An equal number of patients were randomized to PG11680 or placebo (n = 125 and 128, respectively), and the sample groups were well balanced with respect to confounding factors such as age, gender, and medication history. Over 90% of the patients underwent percutaneous coronary interventions. The echocardiographic determined LV end-diastolic volume at baseline (initial post-MI measurement at time of randomization) was compared with that obtained at 90 days and was the focused primary response variable. As a composite, LV end-diastolic volumes increased slightly from baseline (10%) at 90 days. The relative degree of LV dilation, as a function of baseline values, was 8.4% in the PG11680 group and 10.3% in the placebo group, which did not reach statistical significance by t-test (P = 0.31). There were nine deaths or recurrent MI in the treated group and five deaths or recurrent MI in the placebo group (P = 0.17). Overall musculoskeletal complaints were similar between treatment and placebo groups (21 and 15%, P = 0.33, respectively). However, seven patients in the treatment group complained of joint stiffness, whereas this complaint appeared to be absent in the placebo group. The authors concluded from this study that, overall, PG11680 was well tolerated in post-MI patients but that no significant effects were observed with respect to LV remodeling.

Thus the outcomes from this clinical study utilizing a selective MMP inhibitor in post-MI patients appeared equivocal. The initial outfall from this study was the closure of a number of development programs for MMP inhibitors, and in particular that for PG11680. The longer term consequences from this initial clinical study are yet to be fully realized, but the near future for developing pharmacological strategies for MMP inhibition in the clinical context of cardiovascular disease is certainly in question. Nevertheless, since the MMP system clearly causes cardiovascular remodeling, then alternative pharmacological approaches such as using doxycycline as an MMP inhibitor remain in clinical evaluation (47). In addition, MMP inhibitors with a highly specific inhibitory profile continue to be developed and refined (83, 93, 99, 172, 357).

However, there are some important lessons that can be learned from this initial clinical MMP inhibitor study. First, these results underscore the complexity of translating basic studies into clinical therapeutics in general. Second, this study emphasizes the complexity and diversity of the MMP system. The reasons for the neutral finding in the clinical study are likely to be multifactorial and include an inadequate dosing regimen, a minimal change in the primary response variable, experimental design issues, and unanticipated pharmacological effects. With respect to the dosing regimen, it is unlikely that this study achieved significant therapeutic efficacy of PG11680 in a large number of patients. Specifically, if the pharmacokinetics from the pig studies using a similar PG11680 formulation (Fig. 29) are combined with the known volume of distribution data for humans (44), then it is possible to model the plasma levels of this MMP inhibitor that would have been achieved in this clinical study. The predicted plasma levels for PG11680 given as an oral dose twice daily and that for a single daily dose are shown in Figure 30. While the twice daily dose yielded a predicted plasma level of PG11680 that oscillated within an effective inhibitory range for many MMP types, the single daily dose fell well below an effective inhibitory concentration of any MMP type for durations of 12 h each day. Another means by which to compare the dosing regimens for PG11680 in the preclinical pig MI studies and the clinical study would be to normalize the dose on a body weight basis (mg of drug/kg body wt). If this is considered, then the clinical dose was approximately fourfold lower than that reported to be effective for achieving a LV remodeling effect in pigs post-MI (525). The primary end point of this clinical study was LV remodeling as defined as changes in LV end-diastolic volume (168). The sample size and power of the study was predicated upon PG11680 reducing LV end-diastolic volume by over 4 ml/m². However, in this study, the relative magnitude of post-MI remodeling as a function of changes in LV end-diastolic volume was modest. Specifically, the absolute change in LV end-diastolic volume over the entire observation period was 5 ml/m². Thus, based on the initial power estimates, it would be necessary for PG11680 to reduce the change in LV end-diastolic volume during the post-MI period by 80% compared with placebo values. These dramatic reductions in LV end-diastolic volumes were never achieved in preclinical animal studies despite optimal dosing conditions and experimental designs. Another important consideration is that patients were treated with standard of care pharmacological therapies that included -adrenergic receptor blockade and ACE inhibitors. Interruption of these neurohormonal pathways, as discussed in the next section, could in and of themselves reduce MMP levels. Thus, adding PG11680 to this background therapy may not have achieved a biological effect, since MMP induction had already been suppressed. Unfortunately, MMP plasma levels or other indices of MMP activation were not assessed in this clinical study, and this issue remains speculative. There exists some in vitro evidence (61, 255), and in particular that from human myocardial fibroblast culture systems, that suggest chronic exposure to an MMP inhibitor will cause an increase in MMP synthesis. Specifically, increased exposure of adult human myocardial fibroblasts to MMP inhibitors caused increased release of MMP-9. With the use of transgenic constructs, it has been established that MMP-9 is an important MMP type in the early post-MI remodeling process (98, 161). Thus, whether and to what degree chronic MMP inhibition, particularly at low or below therapeutic doses such as those used in the PREMIER study, may actually induce MMP synthesis and release remains a point of concern. In the animal studies utilizing MMP inhibition in the post-MI period, particularly that for the selective MMP inhibitor, MMP inhibition was instituted at 5 days post-MI (8, 525). This was predicated upon past clinical observations suggesting that interference with the early wound healing response post-MI was associated with adverse consequences (129, 199, 397). In the PREMIER study, MMP inhibition was instituted within 24 h of the onset of the MI and, therefore, was in place during the initial wound healing period. Therefore, in addition to the dosing regimen, the timing of selective MMP inhibition also varied from the preclinical post-MI studies. It is unclear if early institution of MMP inhibition may have affected the initial LV remodeling process as the primary comparisons of LV geometry were performed at 30 and 90 days post-MI.

View larger version (18K): [in this window] [in a new window]   FIG. 30. Predicted plasma levels for the selective MMP inhibitor PG116800 based on the dosing regimens in the clinical post-MI study (premier). This study initially utilized a twice daily oral dose of this compound, but this was reduced to a single daily dose at 1 mo post-MI. With the use of the known pharmacokinetics for this compound, the twice daily dosing protocol (top) would fall within the effective inhibitory concentration (IC50) for a number of MMP types, but due to the half-life of this compound, never reach a steady-state inhibitory level. With the single daily dosing protocol (bottom), a loss of effective MMP inhibition likely occurred for extended periods of time. (Predicted plasma levels were determined based on available pharmacokinetic data from Refs. 44, 168, and 525 and with the kind assistance of MUSC pharmacology graduate student Rachel Ford.)

As detailed in previous sections, biological as well as mechanical signals can induce MMP transcription, synthesis, and activation. Therefore, it would follow that inhibition of neurohormonal/inflammatory pathways or alterations in myocardial wall stress would in turn alter MMP levels. For example, inhibition of the renin-angiotensin-aldosterone pathway has been shown to reduce relative MMP levels within the myocardium (211, 227, 376, 380). In a study by Li et al. (227), ACE inhibition or MMP inhibition reduced LV dilation in a rat heart failure model. Moreover, this past study demonstrated that ACE inhibition reduced relative myocardial MMP levels. In a POH model in rats, ACE inhibition reduced the degree of MMP induction and slowed the transition to heart failure (376). In a POH model in mice, an aldosterone antagonist reduced myocardial MMP-2 levels (211). Interestingly, studies have examined the combinatorial effects of inhibition of the renin-angiotensin-aldosterone pathway and MMP inhibition. In the rapid-pacing model of DCM, ACE and MMP inhibition imparted an additive effect on myocardial structure and function (271), but these initial findings have not been extended to other models of LV remodeling. In another study using the rapid pacing model, it was demonstrated previously that -adrenergic receptor inhibition altered local myocardial MMP levels (393). A past study demonstrated that endothelin receptor inhibition can modify myocardial MMP levels in a post-MI rat model (338). A large number of studies have demonstrated that modifications in mediators of inflammation can reduce local MMP levels (39, 71, 193, 197, 221, 228, 325, 344, 401, 425). A clear link has been established between TNF receptor inhibition and MMP induction in a number of animal systems of LV remodeling (39, 193, 344, 425). Other pharmacological interventions that may attenuate local inflammatory pathways such as statins have also been demonstrated to modify MMP levels (171, 461). Finally, modifying myocardial mechanical load has also been shown to reduce the pattern and magnitude of MMP levels within the remodeling myocardium (31, 206, 230, 375). As detailed previously, LV unloading in DCM patients by mechanical assist reduced myocardial MMP levels (206, 230). With the use of a passive myocardial restraint device, myocardial MMP levels have been altered in animal models of MI and ischemic DCM (31, 375). Taken together, the therapeutic armamentarium that is currently available for patients with LV remodeling, as well as emerging therapies, are likely to have effects on critical MMP transcriptional pathways.

	VII. MONITORING MATRIX METALLOPROTEINASE LEVELS AND ACTIVITY

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As outlined in previous sections, past studies regarding the relationship between LV remodeling and MMP levels were based on myocardial sampling approaches. However, there are a number of limitations with this approach. First, myocardial samples are subjected to homogenization and processing that disturb normal matrix architecture and organizational relationships between MMPs and TIMPs. Second, myocardial measurements are often done using detergents or emulsifying agents that cause destruction of critical sulfide bonds and the "cysteine switch" mechanism of activation (66, 281, 293, 322, 464, 472). Thus myocardial measurements of MMPs such as zymography do not reflect actual enzyme activity, but rather provide a relative index of MMP abundance. Third, myocardial measurements of MMPs are not well suited for serial studies, since repeated myocardial sampling can be problematic. As a result, myocardial sampling results in an in vitro assessment of relative MMP and TIMP levels at one point in time and may not necessarily reflect the dynamic nature of this proteolytic system. Fourth, myocardial sampling is not readily amenable for clinical studies in terms of developing stochastic MMP/TIMP modeling for diagnostic/prognostic purposes or for the evaluation of a specific therapeutic intervention. As an example, the PREMIER study was hampered by not having a means by which to assess the relative degree of MMP inhibition on MMP/TIMP abundance or activity (168, 332). In light of these limitations and the need to develop strategies for monitoring MMP levels/activity in the intact system, several strategies have been developed. These strategies include MMP/TIMP plasma profiling, in vivo measurement of myocardial interstitial MMP activity by microdialysis (91, 103), as well as through imaging modalities.

A. Plasma Profiling and Surrogate Markers

1. Plasma profiling post-MI

Due to the increased availability of antisera directed against specific MMP and TIMP types, quantification by immunoassays of plasma samples has become possible in the clinical research setting. The first application of MMP/TIMP plasma profiling was with acute coronary syndromes and MI (119, 164, 174, 175, 186, 187, 253, 264, 411, 459, 461, 476, 485). For example, Kai et al. (187) reported an early increase in plasma MMP-9 levels that were coincident in patients with acute coronary syndromes. While the exact time point in which increased plasma MMP-9 levels occurs in patients undergoing myocardial ischemia and MI remain to be fully elucidated, it does appear to be associated with coronary plaque rupture (119). Moreover, the increased MMP-9 levels appear to be emerging from the cardiac circulation as a significant aortic-coronary sinus gradient has been reported in patients undergoing catheterization and acute coronary syndromes (174). A similar pattern of increased release of MMP-3 from the coronary circulation has also been reported in patients with acute myocardial ischemia (175). While increased levels of specific MMP types have been reported early following myocardial ischemia, plasma TIMP levels do not follow the same pattern (164, 186, 485). For example, relative TIMP-1 levels do not match the increase in MMP-9 levels in patients post-MI, and therefore, this results in an elevated MMP-9/TIMP-1 ratio. The temporal pattern for TIMP-4, which is robustly expressed within the cardiovascular system, was examined in patients up to 6 mo following MI (485). In this study, a robust increase in plasma MMP-9 was observed early in the post-MI period and was accompanied by a reduction in TIMP-4 levels. As shown in Figure 31, plasma concentrations of TIMP-4 fell below reference normal values early in the post-MI period. The plasma MMP-9/TIMP-4 ratio was increased for up to 6 mo post-MI. One potential net effect of this relative reduction in MMP inhibitory control in this post-MI period would be an increase in overall matrix degradation. Plasma profiling MMPs, along with other biomarkers of LV remodeling such as brain natriuretic peptide and troponin, have been performed in post-MI patients (253, 459). Tziakas et al. (461) reported that brain natriuretic peptide synthesis was associated with MMP-9 levels in the early post-MI period. However, troponin levels, indicative of the extent of myocardial injury, appear to be only weakly related to plasma levels of MMPs (459, 485). This would suggest that the degree of matrix remodeling that occurs in the post-MI period is independent of the extent of myocyte loss and myocardial injury. Indeed, changes in plasma levels of MMPs in the post-MI period are emerging as an independent predictor of the degree of adverse LV remodeling and progression to heart failure (264, 411, 476, 485). For example, our laboratory has demonstrated that the magnitude of the plasma MMP-9 level in the early post-MI period was associated with LV dilation that occurs at 3 mo post-MI (485). In a study by Wagner et al. (476), the early increase in MMP-9 levels was associated with an increased risk of the later development of heart failure (odds ratio of 6.5, P < 0.006). Thus plasma profiling of MMPs and TIMPs in patients post-MI is likely to hold prognostic and diagnostic importance. However, whether and to what degree modifying these changes in plasma MMP/TIMP profiles in the post-MI period may beneficially alter the course of LV remodeling and the risk of heart failure remains to be established.

View larger version (10K): [in this window] [in a new window]   FIG. 31. Left: plasma profiles for TIMP-4, which is robustly expressed within the cardiovascular system, was examined in patients following MI. TIMP-4 plasma concentrations fell below normal reference values early post-MI and remained in the low range of normal for the entire follow-up period. Right: an early and robust increase in MMP-9 levels was observed in patients post-MI, and the relative ratio of MMP-9/TIMP-4 plasma levels was computed for the 6-mo follow-up period. A persistently elevated MMP-9/TIMP-4 ratio was observed which would favor increased matrix proteolytic activity. [From Webb et al. (485).]

Since changes in the LV myocardial matrix are a fundamental structural event in the progression of overload states such as POH, MMP/TIMP plasma levels have been examined in this clinical context (3, 5, 247, 259, 343, 436, 438, 439, 538). One of the analytes that has been the subject of measurement in patients with hypertension and POH has been TIMP-1. Uniformly, past clinical studies have reported a dramatic increase in plasma TIMP-1 levels in patients with POH (3, 5, 247, 436, 438, 439). Interestingly, the increased plasma TIMP-1 levels are not necessarily unique to elderly patients with essential hypertension, but also occur in younger women with gestational hypertension and POH (436). These observations would suggest that increased TIMP-1 levels may be an important biological event in changing myocardial matrix turnover, which in turn would influence myocardial physiological properties. Indeed, a significant relationship has been demonstrated between the changes in TIMP-1 levels to indices of myocardial relaxation (3, 439). For example, Tayebjee et al. (439) reported that a negative correlation existed between plasma TIMP-1 levels and Doppler measurements of LV relaxation. In a study by Ahmed et al. (3), a significant relationship between indices of LV diastolic function and symptoms of heart failure were reported in hypertensive patients with respect to specific MMP/TIMP plasma profiles. Specifically, in this past study, detectable levels of MMP-13 were reduced in patients with POH, whereas plasma TIMP-1 levels were slightly increased. This would result in a net reduction in myocardial matrix proteolytic activity. Moreover, as shown in Figure 32, the highest levels of plasma TIMP-1 levels were observed in patients with POH and symptoms of heart failure. Further evidence to suggest that plasma levels of TIMP-1 are reflective of changes in the structure and function of the myocardial matrix comes from studies that measured indices of collagen synthesis and degradation (5, 247). For example, Alla et al. (5) demonstrated that collagen type I propeptide levels, indicative of collagen synthesis, were increased in patients with POH, whereas collagen type I telopeptides, indicative of collagen degradation, were actually suppressed. Indeed, using surrogate plasma markers of collagen metabolism, the Diez laboratory demonstrated an increase in propeptide markers of myocardial matrix synthesis and a reduction in propeptide markers of degradation in patients with POH and heart failure (247, 343). Finally, it has been demonstrated that pharmacological interventions such as the use of calcium channel antagonists can modify MMP/TIMP plasma levels in hypertensive patients (259, 538). In summary, these studies suggest that plasma profiling surrogates of matrix remodeling in patients with hypertension will yield insight into the natural history of LV remodeling, hold diagnostic/prognostic information, as well as serve as an index of therapeutic efficacy.

View larger version (10K): [in this window] [in a new window]   FIG. 32. Plasma TIMP-1 levels were quantified in age-matched patients with no history of hypertension (control, n = 39), patients with hypertension (HTN) but no LV hypertrophy (n = 14), patients with LV hypertrophy (LVH) but without symptoms of heart failure (n = 23), and patients with LVH and congestive heart failure (CHF, n = 26). TIMP-1 levels appeared to increase incrementally as a function of the natural history of hypertensive heart disease, with a significant increase in patients with LVH and CHF (*P < 0.05 vs. control, #P < 0.05 vs. LVH with no CHF). [From Ahmed et al. (3).]

Plasma MMP/TIMP measurements have been performed in large cohorts of patients at risk for developing heart failure as well as in patients with established heart failure (57, 74, 126, 427, 428, 502). In patients with heart failure secondary to DCM, increased plasma levels of collagen degradation products have been reported (391). Increased plasma levels of certain MMPs have been reported in patients with DCM, such as MMP-2, MMP-8, and MMP-9 (126, 460, 502). In one study, the plasma levels of MMP-8 and MMP-9 in DCM patients were correlated with the changes in soluble TNF receptor levels (502). Both MMP-8 and MMP-9 can be synthesized by inflammatory cell types and can be induced by cytokines such as TNF. Taken together, the emergence of these MMP types in the plasma of DCM patients suggests that inflammation may be a contributory factor. While the contributory mechanisms for the changes in plasma MMP levels remain speculative, an association between changes in plasma MMP levels to adverse LV remodeling is beginning to emerge. For example, in a Framingham Heart substudy, it was demonstrated that increased plasma MMP-9 levels were associated with LV dilation (427). Specifically, as shown in Figure 33, higher plasma levels of MMP-9 were associated with an approximately twofold higher risk of adverse LV remodeling. Changes in the plasma levels of TIMP-1 have been the focus of several large-scale cardiovascular outcome studies (57, 428). In one study of over 1,000 patients, elevated TIMP-1 plasma levels were associated with major cardiovascular risk factors and with the presence of LV hypertrophy (428). Furthermore, changes in plasma TIMP-1 levels have been associated with increased mortality (57). However, it is likely that the changes in plasma MMP and TIMP levels observed in these past survey studies will be influenced by the underlying etiology of the cardiovascular disease process, and therefore, future stratification studies will be necessary. Furthermore, these past large-scale studies only measured MMP and TIMP plasma levels at one point in time, and how the temporal relation to the natural history of the LV remodeling process and progression to heart failure remains to be established. Nevertheless, these studies do provide further evidence to support the potential utility of plasma MMP and TIMP profiling in terms of prognosis.

View larger version (12K): [in this window] [in a new window]   FIG. 33. Plasma levels of MMP-9 were measured from 699 patients enrolled in the Framingham Heart Study. These plasma measurements were related to indices of LV geometry, such as LV end-diastolic dimension. With the use of a binary model approach for plasma MMP-9 and logistic regression, elevated MMP-9 levels resulted in an over 2-fold risk for increased LV end-diastolic dimension. Specifically, when adjusted for age, and other covariates, increased plasma MMP-9 was associated with a higher risk of LV remodeling. [Data from Sundstrom et al. (428).]

As with any blood-derived biomarker, MMP and TIMP plasma levels only serve as surrogate markers of a localized process that is occurring within remodeling tissue structures. Thus this approach is dependent on adequate spillover from interstitial compartments. Because MMP and TIMP interactions are tightly regulated at the site of proteolytic targets, then egress of certain MMPs and TIMPs into the plasma may not occur and results in an incomplete profile. This is most certainly true for the MT-MMPs in which relative levels of expression and activity will not be directly reflected by plasma assays. In addition, the release from the interstitial compartment may not be in a proportional manner to local interstitial levels or activity. This is particularly true for certain MMPs such as MMP-1 and MMP-13 in which very low or nondetectable levels may exist in the plasma (3, 38, 175, 427, 437, 485, 502), but abundant levels for these MMP types can be measured from myocardial samples. Thus plasma levels for MMPs and TIMPs may not be reflective of local tissue concentrations. Plasma profiling in a serial fashion can provide some insight into the stochastic nature of MMPs and TIMPs and potentially overcome some of the limitations with respect to the interpretation of a single set of values at one point in time. However, to date, this has been rarely performed in clinical studies. Another interpretative limitation of plasma MMP/TIMPs is that these measurements do not reflect proteolytic activity. First, MMPs do not circulate within the vascular compartment in an active form but rather form complexes to proteins such as albumin and -macroglobulin (139, 292, 293, 472, 504, 507). Second, plasma will contain both proforms, active, and lower molecular weight forms of MMPs which are not only complex to these plasma proteins but also to TIMPs. Thus the measurement or inference of MMP activity from plasma assays is problematic and can give rise to confusion with respect to data interpretation.

With the use of immunologic-based assays, it is possible to measure total plasma levels of MMP and TIMP types, and thereby determine total relative abundance. However, the interpretation of these results with respect to net proteolytic activity that may occur in the myocardium is at best an indirect determination and must be done with extreme caution. Because multiple protein structures of an MMP type can exist within the plasma, then the sensitivity and the specificity of the immunologic reagents utilized must be carefully scrutinized. In many of the clinical reports outlined in the previous section, these analytical considerations were not presented. Thus intrastudy comparisons of absolute values for plasma concentrations of MMPs and TIMPs are not yet possible. This makes interpretation of plasma MMP/TIMP profiles difficult with respect to standardizing reference control values. This is of particular importance, since plasma MMPs and TIMPs can be affected by confounding variables such as age, gender, and ethnicity (437). Since it is becoming apparent that plasma MMP/TIMP profiling may hold relevance with respect to prognosis and diagnosis, then standardization of analytical methods and establishing reference normal concentrations for subpopulations of patients would be an important advancement for clinical research.

The final and probably one of the most important considerations and limitations of plasma MMP/TIMP profiling is that of the actual source of the analytes. MMPs and TIMPs are synthesized within a wide variety of tissue types, and therefore, changes in plasma MMP/TIMP levels may not necessarily reflect changes occurring within the myocardium. This is of a particular concern in patients that are encumbered by multiple disease processes such as rheumatological disorders or cancer. Many of the clinical studies performed to date have attempted to control for these potential confounding factors through the use of exclusion criteria; however, this will remain a concern with larger scale studies. Interestingly, the large-scale studies to date that have not set up rigorous exclusion criteria have identified that certain changes in plasma MMP/TIMP levels remain predictive of myocardial remodeling or cardiovascular events (427, 428). Thus it is likely that a certain portfolio of plasma MMP/TIMP measurements may be more specific and sensitive to myocardial remodeling processes. Identifying this cassette of plasma MMP/TIMPs that can be used to identify an ongoing myocardial remodeling process in the context of patients with multiple chronic disease processes will be an essential step for clinical applications. With respect to demonstrating that changes in plasma MMP/TIMP levels can be reflective of a myocardial source has been established from several studies (139, 174, 215, 422). Lalu et al. (215) measured both right atrial and plasma MMP-2 and MMP-9 levels in patients undergoing cardiac surgery. In this study, equivalent directional changes in myocardial and plasma MMP-2 and MMP-9 levels were reported. Inokubo et al. (174) reported that the changes in plasma MMP profiles that occurred in patients with acute coronary syndromes were directly reflective of myocardial production based on aorto-coronary sinus gradients. In past work from this laboratory, targeted myocardial infarction was induced in patients with hypertrophic obstructive cardiomyopathy, and changes in plasma MMP/TIMP profiles were determined (38, 422). These patients were free from a number of other confounding medical conditions, and since the precise time point in which the myocardial injury was known, it provided a unique opportunity for temporal profiling plasma MMP/TIMP levels. Representative profiles for MMP-9 and the MMP-9/TIMP-1 ratio are shown in Figure 34. Since baseline (prior to myocardial injury) samples could be obtained, then relative changes could be examined. Plasma MMP-9 increased robustly within 8 h and remained elevated for up to 60 h after myocardial injury. In contrast, TIMP-1 levels did not increase in a concomitant fashion and resulted in an elevated MMP-9/TIMP-1 ratio within this early period following myocardial injury. In a study by Lopez et al. (247), it was demonstrated that increased plasma TIMP-1 levels in hypertensive subjects were directly related to the degree of myocardial fibrosis as assessed by concomitant biopsy. These past studies demonstrated that changes in plasma MMP/TIMP levels can be reflective of specific events occurring within the myocardium. Finally, for plasma profiling, more specific biomarkers of cardiovascular remodeling will further improve specificity of this approach, such as measuring TIMP-4 (3, 422, 485). Thus coupling temporal profiling of a specific cassette of MMP/TIMPs that are unique to a specific myocardial remodeling process (i.e., ischemic vs. hypertrophic) to those with a high cardiovascular prevalence will be likely areas for future clinical research.

View larger version (14K): [in this window] [in a new window]   FIG. 34. Plasma levels for MMP-9 and TIMP-1 were measured in 51 patients undergoing controlled MI to relieve subaortic stenosis secondary to hypertrophic obstructive cardiomyopathy. In these patients, plasma was collected at baseline and up to 60 h following ethanol injection into the septal coronary artery. This approach resulted in an MI of the septal region and caused significant changes in MMP/TIMP profiles. Plasma MMP-9 increased by 6-fold at 8 h following alcohol-induced MI and remained elevated for up to 60 h postinjection. Plasma TIMP-1 levels did not follow a similar temporal pattern and remained lower than relative MMP-9 levels. Thus the plasma MMP-9/TIMP-1 ratio was increased following ethanol injection and would be suggestive of higher proteolytic activity within the myocardium (*P < 0.05 vs. baseline). [Data from Bradham et al. (38).]

In light of the fact that defining MMP activity in vivo holds great clinical significance in both cancer and cardiovascular disease, recent effort has been placed in developing nonpeptide markers for MMP activity (153, 154, 381, 423, 467, 477). In general terms, these markers utilize a backbone structure of the broad-spectrum MMP inhibitors reviewed in a previous section. With the use of this approach, a number of radiolabeled and spin-labeled compounds have been developed that allow for visualization of MMP activity (153, 154, 381, 423, 467, 477). Due to the fact that these are single-dose studies and due to the transient nature of the intravenous injection, these imaging agents do not confer significant MMP inhibition. However, this does provide a means to directly visualize and assess the relative degree of MMP activation at a specific site of interest. For example, this approach was utilized to visualize MMP activation surrounding carotid artery plaques in a hyperlipidemic mouse model (381). An example of radiolabeled MMP radiotracer constructs developed for post-MI imaging is shown in Figure 35. The clearance kinetics and binding characteristics of this MMP radiotracer construct have been fully characterized (423). Moreover, this MMP radiotracer construct was utilized in a murine post-MI imaging study (423). Specifically, these imaging studies utilized an MMP radiotracer, ^99mTc-RP805. Characterization of RP805 with respect to binding to MMP-2, -3, -7, -9, -12, and -13 was performed using recombinant human MMP constructs that demonstrated nanomolar binding affinity. To determine the applicability of this MMP radiotracer, mice underwent coronary ligation, and imaging studies were performed at 1, 2, and 3 wk post-MI. All mice underwent static pinhole micro-gamma/X-ray computed tomography (SPECT) at 75 min after intravenous injection of 1.3 mCi of the ^99mTc MMP radiotracer. This was followed by intravenous injection of 0.25 ± 0.05 mCi of thallium-201 (²⁰¹Tl), and repeat dual isotope pinhole microSPECT/CT imaging was performed. Reconstructed microSPECT images were oriented according to the CT anatomical images. Representative images are shown in Figure 35. ²⁰¹Tl images demonstrated a large anterolateral perfusion defect in the post-MI mice. The ^99mTc-RP805 pinhole microSPECT images demonstrate focal uptake of tracer in the area of the ²⁰¹Tl perfusion defect, which could be quantified (in this example a relative 250% increase at both 1 and 3 wk post-MI, indicative of increased MMP activity at the site of the MI). While these are only proof of concept studies, it appears that targeted MMP tracer imaging will provide a novel noninvasive approach for evaluation of MMP-mediated myocardial remodeling and may have important clinical implications for evaluating new therapeutic interventions designed to alter this process.

View larger version (68K): [in this window] [in a new window]   FIG. 35. Top: an example of a radiotracer constructed to bind to the active catalytic domain of all major MMP types. In this instance, the backbone of the radiotracer is that of a generic MMP inhibitor and is ligated to the radioisotope indium. However, other radioisotopes can be utilized in this construct such as technetium (99mTc) which are amenable to in vivo imaging. Bottom: dual-isotope imaging studies were performed in which the MMP radiotracer 99mTc-RP805 was intravenously injected followed by the perfusion imaging agent thallium (201Tl). These imaging studies were performed in mice using a microSPECT/CT system allowing for geometric registration of the LV to the radioisotope signal. The dashed circles indicate the short axis orientation of the LV. In control mice, a homogeneous 201Tl signal (green) could be appreciated throughout the LV short axis with minimal uptake of the 99mTc MMP radiotracer (red). However, following MI induction in mice, a clear defect in the 201Tl signal could be appreciated that was accompanied by increased 99mTc MMP radiotracer signal (as shown by the yellow arrows). The increased signal for the MMP radiotracer is indicative of heightened MMP activity that occurred in and around the MI. [From Su et al. (423).]

	VIII. FUTURE DIRECTIONS AND CONCLUSIONS

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The previous sections provided only a brief outline of the number of stimuli that induce changes within the myocardial interstitium. It is certainly clear that biological and mechanical signals that contribute to the regulation of cardiac cell growth also play a predominant role in the regulation of matrix degradation pathways. Thus interventions that are employed to alter myocardial cell growth and function are also likely to influence matrix remodeling pathways through both direct and indirect pathways. This is most certainly the case for the renin-angiotensin-aldosterone receptor pathway (211, 227, 376, 380, 534, 538). Specifically, activation of the angiotensin type 2 receptor is likely to cause a number of intracellular events within the coronary vasculature and myocardial fibroblasts, which will alter MMP/TIMP transcription. However, it is also likely that less examined receptor pathways, such as the bradykinin receptor system, also play a role in transcriptional regulation of MMPs and TIMPs (382, 384). Thus elucidating the specific receptor transduction pathways that regulate transcriptional elements required for MMP/TIMP induction is an important area for future basic research. One potential future avenue of investigation is to move beyond receptor agonist/antagonist approach and target intracellular signaling elements and transcriptional process directly. For example, a ubiquitous intracellular signaling family is the PKCs. Defining which PKC isoforms are predominantly responsible for MMP/TIMP transcription may provide important insight into what receptor pathways are evoked, but also hold relevance with pharmacological specificity. It is now known that PKC activation and translocation to an effector target site are dependent on specific protein sequences that are highly selective for PKC isoforms (278, 279, 301). These intracellular receptors for activated PKC, RACK proteins(receptors for activated C-kinase), have been sequenced and cloned (278, 279, 301). Studies have demonstrated that small peptide fragments corresponding to the RACK binding site of each PKC isoform can result in selective loss of function of the isozymes. Therefore, small molecule strategies that target and inhibit specific PKC isoforms would in turn likely reduce MMP transcriptional events. This certainly does not imply that PKC holds any predominant role in the regulation of MMP/TIMP transcription, but simply serves as one example of how modifying specific intracellular signaling pathways could potentially alter MMP/TIMP transcription. Another future strategy that would define which signaling/transcriptional pathways are obligatory for MMP/TIMP induction would be to interrupt the synthesis of transcription factors. For example, it may be possible to cause posttranscriptional silencing of targeted mRNAs through RNA silencing techniques (54, 214, 509). In addition to using the RNAi technique to silence transcription factors operative in MMP/TIMP expression, this approach may also be applicable in targeting specific MMP/TIMP transcripts. For example, using an adenoviral construct and transfection methods, an RNAi sequence targeted against the MMP-9 mRNA was produced in mammalian cells (glioblastoma cell line) (214). In this study, significant inhibition of MMP-9 zymographic activity and indices of in vitro matrix remodeling were achieved through overexpression of a specific RNAi. Thus, while significant issues regarding delivery, stability, and construct design remain to be established, future strategies that target pretranslational events may hold promise as a specific means to regulate myocardial MMP/TIMP expression.

The MMPs and TIMPs must be synthesized and then transported to the cell surface for secretion into the interstitial space or for insertion into the cell membrane. As outlined in a previous section, studies have demonstrated that interrupting posttranslational processing, such as through the furin pathway, can modify MMP protein level and activity (317, 413). Whether there are unique posttranslational points that could be specifically targeted for this point in MMP/TIMP processing would most certainly be a potentially fruitful area of research. Most certainly one of the most popular, but to date arguably the most disappointing, approaches to regulate myocardial matrix degradation is through direct inhibition of active MMPs. Either through pharmacological or adenoviral approaches, recapitulating the effects of endogenous TIMPs has been problematic. This is likely due to the fact that our understanding of which MMPs are causative for adverse LV remodeling as opposed to those essential for normal matrix turnover is in its infancy. Moreover, significant assumptions have been made about how to inhibit MMP activity based on in vitro or murine systems. Thus future directions for the regulation of active MMPs are going to require a careful synthesis of basic concepts of MMP activation with appropriate translational models.

B. Defining the Role of MMPs: Novel Substrates and Function

One of the more exciting avenues of research regarding MMPs is recognition that these proteases do not simply degrade a small portfolio of extracellular matrix proteins. As outlined in a previous section, it is likely that MMPs affect multiple biological signaling pathways and protein structures, which in turn will influence both cellular and extracellular remodeling programs. The portfolio of biological processes that are influenced by MMP activity is likely to grow rapidly through the use of proteomic approaches. However, the larger task of integrating these in vitro degradomic approaches to the intact cardiovascular system will likely be the most difficult, but also constitute the highest yield with respect to understanding the biology of myocardial matrix remodeling. Through these approaches, it is likely that new and novel roles for MMPs are to be realized. As an example, synthesizing some of the current concepts regarding the function of MT1-MMP is shown in Figure 36. Specifically, MT1-MMP will yield localized proteolytic activity against a number of matrix proteins, activate other soluble MMPs, and can process cytokines and growth factors. Thus an induction-activational cascade exists within the myocardium that is highly localized. Another example of the potential diversity of actions of MMPs is the studies that have identified intracellular substrates. Specifically, Sawicki and colleagues (379, 482) have demonstrated intracellular localization of MMP-2 to the myofilaments within the cardiocyte, which can be activated with ischemia-reperfusion. These studies challenge the paradigm that MMP substrates are only extracellular. Understanding the diverse nature and function of MMPs as well as TIMPs in not only matrix remodeling, but in cell growth regulation and viability in general, will likely emerge as a future avenue of discovery.

View larger version (47K): [in this window] [in a new window]   FIG. 36. A schematic emphasizing the multiple functions that MMPs, such as MT1-MMP, likely play in the regulation of myocardial matrix remodeling. First, MT1-MMP is membrane bound, which will result in a localized region of the matrix to be affected. Second, the catalytic domain of MT1-MMP can degrade a large portfolio of matrix molecules that include the collagens, glycosaminoglycans, and basement membrane proteins. Third, MT1-MMP can proteolytically process soluble pro-MMPs to active MMPs. This function will likely amplify and enhance the matrix degradative potential within the myocardial interstitium. Fourth, MT1-MMP can process other biological molecules such as TNF and TGF, and thereby affect signaling cascades and growth regulatory pathways, which can affect both cellular and extracellular form and function. (Figure kindly provided by Dr. Anne Deschamps, Medical University of South Carolina.)

In any comprehensive review of this type, it is compulsory to provide some future directions that the field of matrix remodeling and degradation may take. However, it must be recognized that research into the functional role of the myocardial matrix itself is undergoing a metamorphosis. Specifically, the traditional belief that the matrix is a static structure that provides scaffolding for cells has evolved to one that the interstitium is a dynamic entity that is under constant change and is highly responsive to biological and mechanical stimuli. This particular review focused on one emerging family of interstitial proteases, the MMPs, and the endogenous inhibitors, the TIMPs. A summary schematic of the transcriptional and posttranslational events and interactions of the MMPs and TIMPs is presented in Figure 37. However, an extensive protease domain exists within the interstitium that includes serine and cytsteine peptidases. The classification of this entire system of proteases and basic function literally and figuratively would encompass a massive textbook (14). Thus it must be recognized that other interstitial proteases, such as serine proteases, play prominent roles in myocardial matrix remodeling. Nevertheless, what is clear is that the changes within the matrix affect LV myocardial structure and function in cardiac disease states such as MI, hypertension, and the cardiomyopathies. As our understanding within this field of matrix biology matures, it will likely hold important diagnostic, prognostic, and therapeutic implications in these cardiac disease states. Moreover, it is likely that a new appreciation for the mechanisms of action of current conventional pharmacological agents such as ACE inhibitors and statins will emerge with respect to matrix remodeling. In addition, it is becoming recognized that the structure and function of the interstitium play a critical role in the viability and phenotype of transplanted cells into the myocardium (212, 430). Thus it is likely that improved understanding of myocardial matrix remodeling and degradation pathways will facilitate the development of pharmacological as well as cell-based treatment strategies for LV remodeling.

View larger version (65K): [in this window] [in a new window]   FIG. 37. A simplified schematic of the current concepts regarding the regulation of MMP activity within the myocardial interstitium. A number of biological signals that include both biochemical and mechanical can affect MMP and TIMP transcriptional activity (see Fig. 5). While incompletely understood, a number of posttranscriptional steps are required for insertion of the MT-MMPs into the cell membrane as well as release of soluble MMPs. The activation of the soluble MMPs requires proteolytic cleavage of the prodomain, which can occur by other proteases or by the MT-MMPs. This MMP activation step provides for focal proteolytic activity but can quickly amplify as additional MT-MMPs or soluble MMPs are synthesized. The active MMPs (both MT-MMPs and soluble MMPs) are inhibited by the TIMPs. The MMP and TIMP transcriptional and posttranslational events form a dynamic set of interactions that contribute to the overall structure and function of the myocardial intersitium. (Developed with the kind assistance of Dr. Anne Deschamps, Medical University of South Carolina.)

	GRANTS

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	ACKNOWLEDGMENTS

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This review would not be possible without the dedicated efforts from medical and graduate students that have worked in the author's laboratory over the past two decades; they know who they are. This effort would not have been possible without the dedicated editorial assistance and patience of Nikole Wilbur, and the author is deeply grateful.

Address for reprint requests and other correspondence: F. G. Spinale, Div. of Cardiothoracic Surgery, Medical University of South Carolina and The Ralph H. Johnson Veteran's Affairs Medical Center, 114 Doughty St., Suite 625, Charleston, SC 29403.

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