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Cardiovascular Research 2006 69(3):585-594; doi:10.1016/j.cardiores.2005.12.010
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Copyright © 2005, European Society of Cardiology

What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models?

Stefan Janssens* and H. Roger Lijnen

Department of Cardiology, Center for Transgene Technology and Gene Therapy, Flemish Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium
Center for Molecular and Vascular Biology, K.U. Leuven, Leuven, Belgium

* Corresponding author. Cardiac Unit and Center for Transgene Technology and Gene Therapy, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 344235; fax: +32 16 345990. Email address: stefan.janssens{at}med.kuleuven.be

Received 10 October 2005; revised 8 December 2005; accepted 12 December 2005


   Abstract
Top
 Abstract
1. Introduction
 2. MMPs in the...
 3. MMPs in development...
 4. MMPs in the...
 5. MMPs in the...
 6. MMPs in the...
 7. Conclusions
 References
 
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for extracellular protein degradation in the cardiovascular system. Originally known to play pivotal roles in tissue morphogenesis and wound healing, they have been shown to participate in the complex remodeling processes in blood vessels and the myocardium. The biological activity of MMPs is regulated at different levels: (1) gene expression, (2) activation of precursor proenzyme forms by other MMPs or non-MMP proteins, including thrombin and plasmin, (3) complex formation with surface and extracellular matrix (ECM) components and (4) inhibition by endogenous tissue inhibitors of MMPs, the TIMPs. Murine models with gain or loss of gene function of different MMPs and TIMPS have provided a wealth of experimental data on their critical role in pathological conditions ranging from atherosclerosis, vascular injury, and restenosis to left ventricular function and structural remodeling following chronic pressure and volume overload and ischemia–reperfusion injury.

KEYWORDS Matrix metalloproteinases; Transgenic mice; Left ventricular remodelling; Myocardial infarction; Atherosclerosis; Vascular injury


   1. Introduction
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 Abstract
 1. Introduction
2. MMPs in the...
 3. MMPs in development...
 4. MMPs in the...
 5. MMPs in the...
 6. MMPs in the...
 7. Conclusions
 References
 
Remodeling of the vascular wall and the myocardium in response to hemodynamic changes may occur through a variety of structural adaptations, which result in changes in diameter of the vessels and myocardial cavities. The direction and extent of cardiovascular remodeling is determined by an active and dynamic process in the extracellular matrix that is coordinated via endothelial cell- and infiltrating cell-derived production of growth factors, cellular adhesion molecules and proteinases [1]. Inappropriate remodeling underlies the pathogenesis of major cardiovascular diseases including restenosis, atherosclerosis, and congestive heart failure. Cell migration, infiltration, and tissue remodeling require degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems in concert can degrade most ECM components. Plasmin can only degrade some components of the ECM directly, such as laminin and fibronectin [2], whereas other components such as elastin and collagen are degraded by MMPs. The plasminogen/plasmin system can, however, play a role in the activation of several proMMPs [2,3]. In most of the disease processes, a dynamic interplay between these MMPs and their multifunctional endogenous inhibitors, the TIMPs, will determine phenotypic changes. In the following, we will review the murine models that have significantly advanced our understanding of the role of MMPs and TIMPs in atherosclerosis, vascular injury, myocardial remodeling responses to pressure and volume overload, and ischemia–reperfusion injury. Murine models with either loss or gain of gene function with respect to the different components of the MMP system have been generated via transgenic or gene transfer technology.


   2. MMPs in the response to arterial injury
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 Abstract
 1. Introduction
 2. MMPs in the...
3. MMPs in development...
 4. MMPs in the...
 5. MMPs in the...
 6. MMPs in the...
 7. Conclusions
 References
 
2.1 Expression of MMPs and TIMPs
Vascular interventions for the treatment of atherothrombotic complications may induce site-specific restenosis within the ensuing weeks to months. Arterial stenosis may result from constrictive remodeling of the vessel wall (such as occurring frequently after balloon angioplasty) and/or from accumulation of cells and ECM in the intimal layer (such as occuring predominantly after intraluminal stent application). Members of the MMP family have been shown to play a role in the pathophysiology of both complications.

Proteinases from the MMP system participate in the proliferation and migration of smooth muscle cells (SMC), and in matrix remodeling during arterial wound healing [3,4]. Only MMP-2 appears to be expressed in quiescent SMCs, whereas expression of MMP-3, -7, -9, -12 and -13 is induced in injured arteries [5–7].

To assess the role of the MMP system in SMC migration and neointima formation experimentally, a perivascular electric injury model in the mouse has been used [8]. In this model, surgically exposed femoral arteries are injured perivascularly via delivery of an electric current, which destroys all medial SMC, denudes the injured segment of intact endothelium, and transiently induces platelet-rich mural thrombosis. A vascular wound healing response results characterized by repopulation of the media and accumulation in the neointima of SMC originating from the uninjured borders.

The temporal and topographic expression pattern of MMPs (MMP-2, -3, -9, -12 and -13) after perivascular injury in this model is compatible with a role in ECM degradation and SMC migration [9]. MMP-3 expression after injury gradually increases to reach a maximum at about 2 weeks, a time when both MMP-2 and -3 are detected in {alpha}-actin stained SMC. These data are compatible with increased MMP-2 activity in patients with ischemic heart disease undergoing coronary angioplasty, potentially contributing to vascular remodeling and late restenosis [10]. MMP-9, -12 and -13 are found in macrophages located mainly in the adventitia and only occasionally in subintimal areas.

In addition to the electric injury model, pressure- and flow-induced changes in vascular remodeling and their impact on MMP expression and activity have been studied in mice. First, explanted murine carotid arteries maintained for 3 days in organ cultures at high distending pressures showed increased gelatinase zymographic activity of MMP-2 and MMP-9, associated with an upward shift in the pressure–diameter relationship, and thus increased distensibility [11]. Second, a flow-induced intima–media thickening model of the partially ligated murine carotid artery revealed a comparably increased expression of MMP-2, MMP-9, and TIMP-2 [12]. Taken together, these changing expression patterns of the MMPs in various vascular injury models are highly suggestive of an important role in the pathophysiology of vascular remodeling. However, by virtue of their associative nature, they cannot identify causal roles for the individual proteinases, which is required for developing better therapeutic interventions.

2.2 Studies in genetically modified mice
Contrary to the common belief that MMP-2 and MMP-9 have a similar role in mediating matrix modification, Johnson and Galis observed that MMP-9 and not MMP-2 was necessary for compaction and assembly of collagen by SMCs [13]. However, using MMP-2 and MMP-9 deficient mice they confirmed an important role for both proteinases in the response to injury and observed a significant reduction in SMC invasion in vitro and neointima formation in vivo [14–16,13]. In contrast, mice with MMP-11 (stromelysin-3) deficiency show accelerated neointima formation with significantly increased intima/media ratios 2 to 3 weeks after vascular injury [17]. Similarly, In mice with deficiency of TIMP-1, the intimal areas at 1 to 3 weeks after injury are significantly larger than in wild-type mice, and contain abundant SMC, whereas the medial areas are comparable, resulting in significantly higher intima/media ratios [18] (Table 1). These data thus support a physiological role of TIMP-1 in vascular remodeling, most likely via monitoring of MMP activity [19].


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  		Table 1 Effects of modulated gene expression of different components of the MMP–TIMP system on the response to vascular injury

 
Whereas MMP-2 and MMP-9 knockout mice have a similar response to endovascular electric injury, they clearly differ in the remodeling response to high distending intravascular pressures. Explanted carotid arteries from MMP-2, but not from MMP-9 knockout mice showed an upward shift in the pressure–diameter relationship when subjected to high distending pressures [11]. These data suggest a key role for MMP-9 in hypertensive vascular remodeling.

MMP-9 may also be required for the angiogenic response to leg ischemia following femoral artery ligation [20]. Whereas capillary density doubled and perfusion capacity significantly increased within 14 days in wild-type mice, this adaptive response was deficient in MMP-9 deficient mice. However, Chun et al. investigated the invasive and collagenolytic capacity of endothelial cells in a three-dimensional type I collagen matrix and observed that endothelial cells from MMP-9 deficient mice but also from MMP-2 deficient mice were unable to express invasive and tubulogenic activity, required for proper angiogenesis in this model [21]. In these experiments, MT1-MMP was found to be critically important to confer endothelial cells with tissue-invasive capabilities, suggesting that MT1-MMP may act as a master-switch in the angiogenic response by controlling activation of other MMPs. Clearly, the role and expression patterns of different MMPs depends on the particular experimental vascular injury conditions and may not be generalised across various pathologic conditions.

2.3 Translational studies using MMP system components
Non-selective MMP inhibitors demonstrated antimigratory and antiproliferative effects in vitro and anti-restenotic effects in vivo in several animal models [22,23]. Marimastat inhibits gelatinase activity and reduces neointimal thickening in cultured human internal mammary arteries, a model of arterial intimal hyperplasia [24]. Metalloproteinase inhibition by Batimastat reduces late lumen loss after balloon angioplasty in atherosclerotic minipigs by inhibition of constrictive arterial remodeling, without effect on neointima formation [25]. MMP inhibition by GM6001 blocks in-stent intimal hyperplasia in a rabbit model [26], whereas FN-439 inhibits the high pressure-induced hypertensive remodeling in murine carotid arteries exposed to high distending pressures in organ culture.

Alternative approaches include stromelysin mRNA antisense oligonucleotides which decrease neointima formation of the injured vessel wall in rats via an effect on SMC migration and proliferation [19] and overexpression of TIMP-1, which reduces neointimal hyperplasia in balloon-injured rat carotid arteries [27] and intimal thickening in a rabbit restenosis model [28]. Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits SMC migration and neointimal formation in the human saphenous vein [29]. A hybrid protein consisting of TIMP-1 linked to the receptor-binding amino-terminal fragment of u-PA strongly enhances the inhibitory effect of TIMP-1 on neointima formation, presumably by blocking binding of u-PA to u-PAR and impairing cellular plasminogen activation [30].


   3. MMPs in development of atherosclerosis
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 1. Introduction
 2. MMPs in the...
 3. MMPs in development...
4. MMPs in the...
 5. MMPs in the...
 6. MMPs in the...
 7. Conclusions
 References
 
Atherosclerotic lesions initially consist of fatty streaks that develop into fibroproliferative lesions. A mature lesion consists mainly of foam cells, SMCs, a necrotic core and a fibrous cap containing extracellular matrix components. Clinical complications of atherosclerosis are often triggered by rupture of unstable plaques, whereas thinning of the atherosclerotic vessel wall due to elastin and collagen degradation and media necrosis may result in aneurysm formation and bleeding. Proteolysis may contribute to neovascularization and rupture of plaques, or to ulceration and rupture of aneurysms.

3.1 Expression of MMPs and TIMPs
A potential role for increased proteolysis in atherosclerosis is supported by the enhanced expression of t-PA, u-PA and several MMPs in plaques [31,7,32,33]. Several MMP system components (MMP-1, -2, -3 and -9) are expressed in atherosclerotic tissue [5,34,35] and in their active form they may contribute to vascular remodeling and plaque disruption. Stromelysin-3 (MMP-11), an unusual MMP that does not degrade any of the major ECM components, is also expressed in human atherosclerotic lesions and is regulated via CD40–CD40 ligand signaling [36]. Expression of MT1-MMP and MT3-MMP in macrophages and SMC of human atherosclerotic plaques is upregulated by proinflammatory mediators which may contribute to ECM degradation and plaque destabilization [37,38]. Expression of MMP-9 is upregulated and that of TIMP-1 downregulated in human monocyte-derived macrophages by oxidized low-density lipoprotein, suggesting that these may contribute to matrix degradation in the atherosclerotic plaque, predisposing to plaque rupture and/or vascular remodeling [39]. Recently, it has been shown that MMP-2 plays a pivotal role in the oxidized LDL-induced activation of the shingomyelin/ceramide pathway and subsequent activation of SMCs [40]. Moreover, interleukin-8 downregulates TIMP-1 expression in cholesterol-loaded human macrophages and may affect the stability of atherosclerotic plaques and thus play a potential atherogenic role [41]. In contrast, regulated expression of TIMP-3, in addition to TIMP-1 and TIMP-2, was shown to counteract MMP activity in atheroma and hence to influence plaque stability [42].

Regional and lesion-specific differences in expression of MMPs/TIMPs may determine the evolution of advanced atherosclerotic plaques and contribute to their vulnerability. Thus, MMP-1 and -3 are more expressed in human aneurysmatic lesions than in occlusive plaques, whereas MMP-9 is mainly detected in carotid as compared with femoral arteries, and TIMP-1 is associated with arterial calcification [43]. Leukocyte-derived MMP-9 is associated with aortic wall degeneration and aneurysm formation [44]. Serum levels of MMP-3 and -9 and of TIMP-1 are elevated in asymptomatic hyperlipidemic subjects at high cardiovascular risk, and MMP-3 and TIMP-1 levels are strongly positively associated with the presence of carotid lesions [45]. Measurement of serum MMP-9 levels may represent a novel marker of inflammation in patients with coronary artery disease and might provide an index of plaque activity [46].

It should also be kept in mind that several members of other classes of proteases are expressed and regulated in atherosclerotic lesions (e.g. serine, cysteine and aspartic proteases and neutrophil elastases) and may contribute to ECM remodeling [47,48].

3.2 Studies in genetically modified mice
In the atherosclerosis susceptible ApoE–/– mice, expression of MMPs in atherosclerotic lesions depends on the size of the lesion but also on the genetic background (Table 2). Thus, C3H/HeJ Apo E-deficient mice show increased MMP-2 and -12 activity in aortas and macrophages compared with those of C57Bl/6 ApoE–/– mice. MMP-9 activity is comparable in aortic tissues of the 2 strains but is higher in macrophages from C3H/HeJ ApoE–/– mice [49].


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  		Table 2 Effects of modulated gene expression of different components of the MMP–TIMP system on atherosclerotic lesion development

 
The hypothesis that MMP-3 may play a role in development and progression of atherosclerotic lesions and in aneurysm formation, was tested in mice with deficiency of ApoE (ApoE–/–:MMP-3+/+) or with combined deficiency of ApoE and MMP-3 (ApoE–/–:MMP-3–/–), kept on a cholesterol-rich diet [50]. Atherosclerotic lesions throughout the thoracic aorta are significantly larger in ApoE–/–:MMP-3–/– than in ApoE–/–:MMP-3+/+ mice, and contain more fibrillar collagen. Aneurysms in the thoracic and abdominal aorta are less frequent in ApoE–/–:MMP-3–/– than in ApoE–/–:MMP-3+/+ mice. MMP-3 may thus on the one hand promote aneurysm formation by degrading the elastic lamina, and on the other hand contribute to plaque stabilization by facilitating smooth muscle cell migration and proliferation following degradation of extracellular matrix components. Immunocytochemistry reveals significantly enhanced accumulation of macrophages in atherosclerotic lesions of ApoE–/:MMP-3+/+ mice and expression of urokinase-type plasminogen activator (u-PA) and MMP-3, colocalizing with macrophages. Zymography confirms the presence of u-PA and MMP-3 activity in extracts of atherosclerotic aortas. These data suggest that plasmin, generated via macrophage-secreted u-PA activates proMMP-3 produced by accumulated macrophages. Taken together, these studies implicate an important role of u-PA in the structural integrity of the atherosclerotic vessel wall, likely via triggering activation of MMPs, and suggest that increased u-PA levels are a risk factor for aneurysm formation [51].

Using the cholesterol-fed apoE knockout mice model, it was recently shown that ApoE–/–:MMP-9–/– plaques are smaller and contain fewer macrophages than ApoE–/–:MMP-9+/+ plaques, whereas MMP-12 deficiency does not significantly affect lesion size or macrophage content. However, both MMP-9 and MMP-12 deficiency protect against atherosclerotic media destruction and subsequent aneurysm formation [52]. These findings contradict the recent observations by Johnson and coworkers using the mouse brachiocephalic artery model of plaque instability. These authors demonstrated that both MMP-3 and MMP-9 are directly involved in atherosclerotic plaque stabilization, while MMP-12 caused lesion extension and plaque destabilization [53]. The reason for the observed differences are unclear but may relate to different genetic backgrounds and experimental conditions.

Moreover, a role for MMPs was identified in the elastin degradation and subsequent calcification of large conduit arteries [54], as peri-adventitial delivery of CaCl2, a known inductor of calcification, proved ineffective in MMP-2- and MMP-9 knockout mice. Similarly, thoracic aortas from MMP-9 deficient mice were protected against thoracic aortic aneurysm formation following topical application of to CaCl2 [55].

A study in mice with combined deficiency of ApoE and TIMP-1 (ApoE–/–:TIMP-1–/–) showed that enhanced MMP activity, as a result of TIMP-1 deficiency, contributes to a reduction of plaque size but promotes aneurysm formation [56]. A similar study confirmed that the atherosclerotic lesions of ApoE–/–:TIMP-1–/– mice develop more aortic medial ruptures in which the elastic lamellae of the media are degraded and infiltrated with macrophages forming pseudo-microaneurysms [57]. In contrast, overexpression of TIMP-1 reduces atherosclerotic lesions in ApoE–/– mice [58] and prevents aortic aneurysm degeneration and rupture in a rat model [59], further substantiating a functional role of MMPs.

Finally, MMP-2 and MMP-9 play a significant role in the process of cardiac allograft rejection as demonstrated in transplantation experiments of BALB/c cardiac allografts into MMP-2 and MMP-9 null mice [60]. Whereas protection against maladaptive LV remodeling was observed in both MMP-2 and MMP-9 null mice, the response following transplantation was markedly different with clearly enhanced allograft survival time in MMP-2 and decreased survival times in MMP-9 null mice. Of interest, differences in survival were correlated with marked differences in cellular infiltration and T-cell responses in both genetic backgrounds.

3.3 Translational studies using MMP system components
Several studies have explored the potential of MMP inhibition in atherosclerosis. Treatment of atherosclerotic cynomolgus monkeys with a broad spectrum MMP inhibitor after (stent)-angioplasty reveals inhibition of angiogenesis but no improvement of artery wall remodeling or intimal hyperplasia [61]. Thus, although a role of MMP system components in development and progression of atherosclerosis is likely, conclusive proof for a causal relation remains missing. The identification of specific proteinases involved in these processes and the development of more specific inhibitors will be required before MMP inhibition can be a therapeutic option [62,63].


   4. MMPs in the pressure-overloaded heart
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 Abstract
 1. Introduction
 2. MMPs in the...
 3. MMPs in development...
 4. MMPs in the...
5. MMPs in the...
 6. MMPs in the...
 7. Conclusions
 References
 
4.1 Expression of MMPs and TIMPs
The induction of an increased afterload to the ventricle is associated with profound changes in myocyte size and alignment, and will over time result in altered ventricular geometry and function. These architectural changes, commonly referred to as ventricular remodeling, are critically dependent upon changes in composition of the extracellular collagen matrix. Modifications in this extracellular support system at the myocardial collagen interface are triggered by altered balances in expression and activity of matrix metalloproteinases and their naturally occurring inhibitors. Increased activity of MMPs results in enhanced degradation of a number of essential ECM constituents, including collagen, fibronectin and laminin, the combined effect of which is further weakening of the support structure and subsequent dilatation of the ventricle with deterioration of LV function. Early investigations in large animal models clearly suggested a role for MMPs in LV remodeling, although the many confounding effects of in vitro zymographic assays did not allow a direct correlation with MMP abundance/immunoblot data and thus identification of the responsible MMP species. The latter limitations, however, can be readily addressed in murine models with targeted loss or gain of specific MMP or TIMP gene functions.

4.2 Studies in genetically modified mice
The functional importance of the MMP system in hypertrophic remodeling following pressure overload has been clearly documented in transgenic mice, with altered gene function of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-3 (Table 3). The first demonstration of the functional role of the extracellular matrix on myocardial performance came from Kim et al. who generated a transgenic mouse overexpressing MMP-1 collagenase driven by the alpha-MHC promoter [64]. Transgenic hearts showed increased LV wall thickness with reduced chamber size and hyperchromatic nuclei in irregularly shaped myocytes with increased myofibrillar width, all consistent with cardiac hypertrophy. The changes that occurred spontaneously were similar to changes in pressure-overload hypertrophy, e.g. following thoracic aortic constriction. Whereas this hypertrophy most likely reflects an initial adaptive myocardial response to preserve LV function in the presence of a chronic pressure overload, constitutive collagenase expression in the heart results in a time-dependent deterioration of left ventricular systolic and diastolic function, as reflected at 1 year by a 47% and 31% reduction in maximum and minimum rates of LV pressure development, (LV dP/dTmax and LV dP/dTmin), respectively. It should be kept in mind, however, that MMP-1 is not normally expressed in mice, except in very early stages of embryogenesis. It remains unclear, therefore, whether these functional changes are solely mediated by a disrupted collagen structure as alternative substrates for the MMP-1 enzyme, including IL-1β may contribute to the observed phenotype. Moreover, constitutive overexpression of MMP-1 may lead to secondary compensatory or adaptive changes which in turn may confound the phenotype [65–67].


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  		Table 3 Effects of modulated gene expression of different components of the MMP–TIMP system on experimental myocardial dysfunction models

 
Another important post-translational regulatory mechanism of MMP activity in the myocardium is through stoichiometric covalent binding to the tissue inhibitors of MMP (TIMP). Because TIMP-3 is the only ECM-bound inhibitor and abundantly expressed in the heart, mice with targeted deletion of TIMP-3 gene function would be expected to mimic in part the phenotype of {alpha}MHC-MMP-1 transgenic mice. However, TIMP-3–/– mice develop spontaneous dilated cardiomyopathy at 21 months of age [68], suggesting alternative biological mechanisms than inhibition of MMPs, possibly inhibition of ADAM and/or ADAMTS family members. Indeed, TIMP-3 is the physiological inhibitor of TNF-{alpha} converting enzyme (ADAM-17) and it is tempting to speculate that increased bioavailability of TNF-{alpha} may contribute to the dilatory phenotype. When TIMP-3 deficient mice are subjected to aortic banding, they develop accentuated hypertrophy and immediate excess in TNF-{alpha}. Double mutant TIMP-3–/–, TNF-{alpha}–/– mice are significantly protected from aortic constriction-induced hypertrophy, chamber size increase and functional deterioration [69], indicating that TIMP-3/TNF-{alpha} is a critical axis leading to pressure-induced left ventricular failure.

Finally, the plasmin/plasminogen system plays a role in myocardial extracellular matrix remodeling either directly or indirectly via activation of pro-MMPs. Mice lacking urokinase-type plasminogen activator and subjected to acute pressure overload (transverse aortic constriction) show only a moderate degree of myocardial hypertrophy and display little cardiac fibrosis and functional impairment [70]. The underlying mechanism for the observed effects is unclear but the observation that MMP-9 deficient mice have an intermediate phenotype with less myocyte hypertrophy and LV wall thickness than wild-type mice, albeit greater than in uPA-deficient mice [70], suggest pleiotropic effects of plasmin in hypertrophic remodeling of the pressure-overloaded left ventricle. Taken together, these data suggest that the remodeling response of the pressure-overloaded heart is a complex interplay between MMP and nonMMP proteins and that biological redundancy will likely preclude targeting of a specific proteolytic enzyme or its inhibitor as a viable therapeutic strategy.

4.3 Translational studies using MMP system components
Studies in transgenic mice have contributed to a better understanding of the molecular bi-phasic response of the heart subjected to an increased pressure load and at risk of progressing from a compensated hypertrophic response to a decompensated dilated state. [71–73]. The very recent observation of a close interaction between TNF-{alpha} signaling and ECM homeostasis in the pressure-overloaded murine heart [69], could in part account for the lack of efficacy of TNF-{alpha}-targeted therapy in decompensated hearts, and may warrant addition of MMP-inhibitors.


   5. MMPs in the volume-overloaded heart
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 Abstract
 1. Introduction
 2. MMPs in the...
 3. MMPs in development...
 4. MMPs in the...
 5. MMPs in the...
6. MMPs in the...
 7. Conclusions
 References
 
5.1 Expression of MMPs and TIMPs
A variety of large animal models has highlighted regional and temporal imbalances in MMPs and their endogenous inhibitors during volume overload following acute myocardial infarction or mitral regurgitation. Again, murine models in contrast offer the exciting possibilities of temporal and to some extent spatial modulation of protease gene function and to study their impact on LV remodeling and contractile performance following MI.

Very recently, the paramount role of MMP activation following myocardial infarction in mice was elegantly evidenced using a near-infrared molecular fluorescent imaging probe that is specifically activated by MMP-2 and MMP-9 [74]. Simultaneous zymographic and RT-PCR studies indicated that MMP-9 expression was induced in the early phase (2–4 days post MI) while MMP-2 induction was more delayed over the course of the first 2 weeks. Dual label confocal microscopy indicated that neutrophils in the infarcted region were the likely celluar source of MMP release. Despite their shared substrates, MMP-2 and MMP-9 therefore play a different role in the myocardial response to ischemic stress and have a distinct temporal expression pattern as also confirmed in the studies of Tao et al. [75,76,13].

5.2 Studies in genetically modified mice
When subjected to LAD coronary artery ligation, MMP-2 and MMP-9 null mice are protected, albeit to varying degrees, from early cardiac rupture following myocardial infarction and from delayed LV dilatation and functional impairment compared with wild-type littermates [77–79] (Table 3). More recently, Matsumura et al. confirmed strong gelatinolytic activity in the infarcted myocardium of control mice and established a causal role for MMP-2 in myocardial rupture, which occurred in 38.5% of control mice [80]. Detailed histological analysis clearly showed that targeted deletion of MMP-2 gene function suppresses disruption of basement membrane components including laminin, fibronectin and type IV collagen but also significantly reduced degradation of the extracellular matrix fibrillar collagen. These authors observed improved survival rates through protection against cardiac rupture, which was associated with a striking delay of phagocytic removal of infarcted cardiomyocytes by macrophages in MMP-2 null mice [80]. These observations are important because they support the mechanistic concept that disruption of the fibrous cytoskeleton but not myocyte necrosis per se determines rupture of the ischemic myocardial free wall. In contrast to earlier observations, they did not find evidence for activation of pro-MMP-9 [78] under these experimental conditions nor for a sustained beneficial effect on long-term LV remodeling and contractile function [79]. The reasons for these divergent observations in MMP-2 null mice are unclear but could be related to the experimental conditions and size of the initial infarct.

Finally, loss of MMP inhibitory control in TIMP-1 null mice is associated with spontaneous LV dilatation, and with worse LV remodeling and augmented contractile dysfunction following myocardial infarction [81,82]. Moreover, loss of TIMP-3 gene function is sufficient to trigger spontaneous LV dilatation, cardiomyocyte hypertrophy and contractile dysfunction at 21 months of age [68]. TIMP-3 null mice have elevated MMP-9 and TNF-{alpha} activity, which contributes to the disrupted interstitial LV matrix, a hallmark of advanced ischemic cardiomyopathy in patients.

5.3 Translational studies using MMP system components
In accordance with several experimental studies, clinical trials have confirmed increased left ventricular MMP activity in the progressive transition from a compensated to a decompensated state and in end-stage heart failure [83,84]. However, while multiple pharmacological approaches with selective or broad spectrum MMP inhibitors have resulted in attenuation of ventricular dilatation in experimental models [85–88], these promising preclinical observations have so far not been successfully validated in clinical studies. A recent phase II, double-blind and placebo-controlled trial of PG-116800, a broad spectrum MMP inhibitor with high affinity to target MMP-2, -3, -8, -9, -13, and -14, in patients with ST-segment elevation myocardial infarction did not find improved post-MI LV remodeling defined as LV end-diastolic volume index change. The treatment was generally well tolerated but did not affect secondary endpoints including re-infarction, development of heart failure, or recurrent ischemia [89]. These data clearly emphasize the need for greater mechanistic understanding before subjecting experimental concepts to clinical testing. More specifically, pertinent questions on the temporal and spatial regulation of MMP expression in the infarcted human heart remain unresolved.


   6. MMPs in the response to myocardial ischemia–reperfusion injury
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 1. Introduction
 2. MMPs in the...
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 4. MMPs in the...
 5. MMPs in the...
 6. MMPs in the...
7. Conclusions
 References
 
6.1 Expression of MMPs and TIMPs
Although MMPs contribute to morphological changes following prolonged periods of I/R [90,91], it was only recently discovered that the activity of MT1-MMP (MMP-14), a member of a specific subfamily of MMPs which is expressed in the myocardium, is increased during I/R in a regional and time-dependent manner [92]. Moreover, when ischemia is prolonged, increased MT1-MMP activity is associated with LV remodeling and can be measured directly in vivo using microdialysis probes and MT1-MMP-specific fluorogenic substrates [92]. At the same time, protein levels of TIMP-4 in the heart were clearly reduced after I/R, consistent with loss of TIMP-mediated control in myocardial ischemia [93–95].

Increased MT1-MMP activity and synthesis and concomitant reduction of TIMP-3 and TIMP-4 in I/R models may suggest a therapeutic role for strategies aimed at inhibiting MT1-MMP or boosting endogenous TIMP levels. This concept was tested in a small number of patients exposed to I/R injury induced by cardioplegia during cardiopulmonary bypass. Atrial biopsies and blood samples before bypass and after removal of aortic cross-clamp clearly showed activation of MMP-2 and MMP-9, and decreased TIMP-1 levels upon reperfusion, predisposing patients to ECM proteolysis and myocardial stunning [96]. Whether or not therapeutic interventions aimed at restoring the protease balance will affect ischemia–reperfusion injury remains to be studied.

6.2 Studies in genetically modified mice
Whereas most transgenic mice deficient in MMPs show a relatively mild phenotype at baseline, MT1-MMP deficient mice have a marked phenotypic disfiguration because of perturbed collagen turnover, leading to postnatal mortality at 3 weeks [97,98]. These data indicate a crucial role for this protease in development. Moreover, its increased abundance and activity in I/R (triggered by biological and mechanical signals) needs to be evaluated in light of its ability to activate a range of other matrix modifying biomolecules, ultimately resulting in increased ECM turnover and LV remodeling.


   7. Conclusions
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Preclinical models of cardiovascular disease in transgenic mice with modulated expression of a variety of matrix-controlling proteinases and their inhibitors undoubtedly provide the basis for a better understanding of their intricate roles in cardiovascular remodeling. However, thus far almost all transgenic models are characterized by unconditional, life-long deletion or overexpression of specific gene functions, unavoidably triggering a series of compensatory or sometimes unanticipated changes in the tightly regulated matrix homeostatic system, which may significantly confound interpretation of genotype–phenotype correlations.

Therefore, important caveats in these murine studies include how to translate observations in genetically modified mice to patients with cardiovascular disease? One approach to do so would be to use gene transfer strategies of individual components of the MMP–TIMP family to the heart or the injured site in the vasculature using direct intracoronary or intramyocardial injections or gene-eluting stent technology and investigate the phenotypic changes at baseline and during relevant stress conditions, including topical injury in blood vessels or pressure and volume overload to the heart. Importantly, further refinement of preclinical models with improved spatial and temporal control of MMP and TIMP gene expression (e.g. organ- or cell-type specific loss or gain of gene function at the time of increased myocardial stress or vascular injury and preferably in a relevant atherosclerotic genetic background) and a better understanding of substrate specificity of the growing number of endogenous MMPs and their inhibitors will be necessary. Greater knowledge of the pathophysiologic role of MMPs and TIMPs in cardiovascular disease will then likely facilitate development of the most appropriate treatment strategies for vasculoprotection and to limit maladaptive left ventricular remodeling.


   Notes
 
Time for primary review 14 days


   References
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 3. MMPs in development...
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 5. MMPs in the...
 6. MMPs in the...
 7. Conclusions
 References
 

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Cardiovasc Res, February 15, 2006; 69(3): 559 - 561.
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