Regulation of Cardiac Extracellular Matrix Remodeling Following Myocardial Infarction.
Jack P.M. Cleutjens
University of Maastricht, Maastricht, The Netherlands
1. Introduction
A three-dimensional structural network of the interstitial, types I and III, collagens forms the structural backbone of the cardiac extracellular matrix (ECM). Other matrix components, including collagens types V and VI, proteoglycans, growth factors and cell-matrix receptors (integrins), can attach to this backbone [1]. The main physiological functions of the ECM are to retain tissue integrity and cardiac pump function, but it is also a dynamic entity which interacts with cells and regulates cell phenotype [2]. Collagen deposition is controlled and can be modulated by hormones, growth factors, cytokines, regulatory proteins and/or hemodynamic forces. Some of these components can be attached to the ECM network [3]. In order to prevent dilatation of the infarcted area, collagen deposition is increased and properly aligned. Excessive accumulation of collagen can lead to diastolic and systolic dysfunction, disturbances in conduction, and can contribute to the development of heart failure.
For normal morphogenesis and maintenance of tissue architecture a balance between extracellular matrix synthesis and degradation is required. An imbalance in the extracellular matrix turnover either by decreased matrix synthesis and/or increased degradation can yield decreased myocardial extracellular matrix content which can lead to cardiac dilatation or even rupture [4]. Extracellular matrix-degrading enzymes expressed after myocardial infarction belong to the families of serine protease and matrix metalloproteinases (MMPs) and are in general secreted as latent proenzymes which need to be activated. The MMPs are the driving force behind myocardial matrix degradation. It is essential to keep the activity of these enzymes under tight control by either influencing the synthesis, activation and/or inhibition by tissue inhibitors of MMPs (TIMPs) or
Recent studies demonstrate that preventing the breakdown of the myocardial extracellular matrix with pharmacological broad spectrum MMP inhibitors in animal models of cardiomyopathy and myocardial infarction yields favorable effects on left ventricular (LV) remodeling. This led to the proposal that MMP inhibitors could potentially be used as therapy for patients at risk for the development of heart failure.
The plasminogen-plasmin system plays a central role in the activation of MMPs. Invasion of inflammatory cells and subsequently the next phases of wound healing are inhibited in plasminogen- or uPA-deficient mice, most likely by the inhibition of MMP activity. Thus regulation of extracellular matrix remodeling either by influencing extracellular matrix synthesis or degradation might be one of the possible prevention mechanisms for cardiac remodeling in the near future.
2. Extracellular Matrix Synthesis
New interstitial collagen synthesis and deposition starts in the infarcted area within the first 3-4 days post-infarction and reaches its maximum at approximately 14 days after infarction. The non-infarcted myocardium is also affected after infarction and interstitial collagen is deposited around the cardiomyocytes and surrounding the coronary vasculature [2]. Over time the increased collagen deposition in the non-infarcted myocardium might further decrease the already impaired cardiac function.
Collagen deposition has a dual effect on cardiac structure and function.
Increased collagen deposition is a prerequisite for preventing dilatation of the infarcted area. However, excessive accumulation of collagen in the infarcted and non-infarcted myocardium leads to increased tissue stiffness, increases the incidence of arrhythmias, and adversely affects myocardial viscoelasticity, which leads to ventricular diastolic and systolic dysfunction and might ultimately contribute to heart failure. Not only the amount of collagen but also collagen cross-linking, localization, and direction and alignment of the collagen fibers in the tissue will determine the contribution to myocardial viscoelasticity.
Collagen is produced and deposited by mesenchymal fibroblast-like cells. In the non-infarcted area collagen is predominantly deposited by fibroblasts whereas in the infarcted area, besides fibroblasts, myofibroblasts contribute to the synthesis and deposition of collagens. The origin of these myofibroblasts is most likely due to differentiation of fibroblasts or pericytes, by gaining smooth muscle-like appearances. The myofibroblasts are not only able to deposit collagen in the infarcted area, but they are also involved in the contraction of the fibrotic area, prevention of dilatation by cell-cell and cell- matrix interactions, and they play a role in the architectural control of scar tissue
formation [5-7]. In contrast to dermal wound healing where all myofibroblasts disappear by apoptosis 3-4 weeks after wound healing, myofibroblasts in the infarct remain, although reduced in numbers, for years in the cardiac scar tissue [8]. This might suggest that the myofibroblasts are actively involved in collagen turnover and fine tuning of scar contraction.
Collagen deposition is controlled by hormonal factors, growth factors, cytokines, regulatory proteins and/or hemodynamic factors [9]. The renin- angiotensin-aldosterone system is one of the main hormonal regulators of fibrosis. Elevation of angiotensin II or aldosterone will increase collagen deposition in both right and left ventricle. Prevention of excessive fibrosis can be achieved by inhibition of these hormones (e.g. angiotensin converting enzyme inhibitors) or inhibition of receptor-ligand binding (e.g. angiotensin type I receptor antagonists) [10]. Besides inhibition, also regression of fibrosis and cardiac stiffness can also be achieved by inhibition of the receptor-ligand binding of angiotensin receptors [11].
A major source of cytokine and growth factor production in the area of wound healing post infarction are the non-cardiomyocytes, e.g., myofibroblasts and endothelial cells. These factors such as tumor necrosis factor-alpha
IL-6, transforming growth factors and
can act via autocrine and paracrine pathways to stimulate collagen synthesis and deposition [12]. Besides growth factors and cytokines other proteins can also be involved in the regulation of collagen synthesis and deposition. Heat-shock protein (Hsp47) is such a protein, which stimulates intracellular procollagen synthesis by interaction with procollagen during its folding, assembly and transport through the endoplasmic reticulum (ER) [13, 14]. Inhibition of cytokines, growth factors or other proteins which stimulate collagen synthesis or deposition might in the future be of interest for clinical application. The use of therapeutics for these factors is not yet well established. The involvement of these interventions with other processes in the body are unknown and the various treatments, either receptor blockers, soluble decoy receptors, or gene transfer have so far only been tested in experimental animal settings. Also models using transgenic or gene-deficient animals are only experimental but can give a good insight into the role of these factors in the remodeling and wound healing process.
Hemodynamic factors alone can regulate cardiac myocyte work and induce cardiomyocyte hypertrophy, but can also stimulate extracellular matrix synthesis. Hypertension leads to thickening of the collagen network (reactive fibrosis), increased stiffness, and impaired cardiac function. The choice of a pharmacological intervention for treatment of heart failure must take into account that not only the extracellular matrix but also cardiomyocytes and non- cardiomyocytes are involved in the remodeling process during heart failure.
3. Extracellular Matrix (ECM) Remodeling
An appropriate regulated balance of ECM synthesis and degradation is required for normal morphogenesis and maintenance of tissue architecture (Figure 1). ECM molecules and their receptors, as well as proteinases and their inhibitors, are all involved in matrix remodeling. An imbalance in ECM turnover either by decreased synthesis and/or increased degradation leads to a decrease of ECM in the myocardium which may lead to cardiac dilatation or rupture.
Figure 1. Graphical depiction of collagen synthesis and degradation (i.e. turnover).
4. Extracellular Matrix Degradation 4.1. Matrix metalloproteinases (MMPs)
Extracellular matrix-degrading enzymes which are activated after
myocardial infarction belong to the families of serine proteases (plasmin, uPA, tPA, thrombin, elastase, cathepsin G) and matrix metalloproteinases. Matrix metalloproteinases (MMPs) are a family of zinc-containing endoproteinases that share structural domains, but differ in substrate specificity, cellular sources, and inducibility. MMPs share several functions: they a) are able to degrade ECM components, b) are in general secreted in a latent proform and have to be activated before they can perform proteolytic activity, c) contain at their active site, d) function at neutral pH, and e) can be inhibited by specific tissue inhibitors of metalloproteinases (TIMPs).
The MMP family can be subdivided into the four groups based on their substrate specificity and primary structure: 1) the collagenases, which are able to cleave fibrillar type I, II and III collagens, which are known to be resistant to cleavage by most other proteinases because they are tightly apposed and consist of highly cross-linked fibrils, 2) the gelatinases, which are able to degrade gelatins and basement membrane type IV collagen, 3) the stromelysins, which are able to degrade a broad spectrum of ECM components, 4) the membrane-type MMPs, which are anchored to the cell membrane by a transmembrane domain and concentrate the proteolytic activity at the cell surface and can activate other MMPs. However, the substrate profiles of the enzymes are more gradual than absolute and besides matrix degradation, MMPs can also act on a variety of non-matrix proteins as well, e.g., activation of growth factors and chemokines [15-20].
4.2. Activation of MMPs
MMPs act at physiologic pH and have certain substrate specificities [2].
The majority of proMMPs are stored extracellularly, bound to different extracellular matrix components. This latent proenzyme pool can be rapidly activated and mobilized upon stimulation [21, 22]. Activated MMPs are able to degrade the complete extracellular matrix. Therefore it is crucial to keep the activity of these enzymes under tight control. This is regulated at several levels.
First of all the MMPs are regulated by transcription, which will ultimately generate a latent enzyme pool. Transcription is controlled by several cytokines, growth factors, corticosteroids and other inducers like Extracellular Matrix MetalloPRoteinase INducer (EMMPRIN) [22, 23] or matrix fragments such as matrikines [22, 24].
Besides transcriptional regulation of MMP mRNA’s, activation of the latent proenzymes is the most crucial step in the regulation of the proteolytic cleavage. The following three different activation mechanisms have been described: stepwise activation, cell-surface-activation by MT-MMPs and intracellular activation [25]. During stepwise activation of MMPs proteinases such as plasmin, trypsin, chymase, elastase or kallikrein are involved. These
proteinases are able to attack the proteinase-susceptible region in the
“propeptide domain” of the MMP, which induces conformational changes in the propeptide and allows the activation site to be cleaved by a second proteinase, usually another MMP [25] or other inducers like EMMPRIN [22, 23].
Cell surface activation of MMPs is considered to be important for pericellular degradation of the ECM during cell migration. The plasminogen system but also the recently cloned membrane-types of MMP (MT-MMPs) are capable of activating MMPs at the plasma membrane [25-28]. Intracellular activation is the third possible activation mechanism. Stromelysin-3 (MMP-11) can be activated by the Golgi-associated subtilisin-like proteinase, furin [29].
Also MT-MMPs are likely to be activated intracellularly [30].
4.3. Endogenous MMP inhibitors
The tissue inhibitors of matrix metalloproteinases (TIMPs) are able to fully inhibit activated MMPs. TIMPs are expressed by a variety of cell types and are present in most tissues and body fluids. The TIMP family consists of four structurally related members, TIMP-1, -2, -3, and -4. TIMPs bind non-covalently to active MMPs in a 1: 1 molar ratio [2]. TIMPs interact with the zinc-binding site within the catalytic domain of active MMPs. TIMP-1 potently inhibits the activity of most MMPs, with the exception of MMP-2 and MT1 -MMP, whereas TIMP-2 is a potent inhibitor of most MMPs, except MMP-9. Besides the role of TIMPs in the prevention of matrix degradation by inhibition of MMP activity, TIMPs are also involved in other biological actions. TIMP-1 and TIMP-2 exhibit growth factor-like activity and can inhibit angiogenesis [31-33], whereas TIMP-3 is involved in the inhibition of apoptosis [34].
Adenoviral human TIMP-1 overexpression in mice led to delayed wound healing, characterized by reduced leukocyte influx, reduced neovascularization, reduced collagen content, larger necrotic areas and a decreased incidence of cardiac rupture [35]. These data suggest that inhibition of MMP activity might be beneficial for cardiac remodeling. However, administration of TIMPs have not been found suitable for pharmacological applications due to their short half-life in vivo .
Besides TIMPs other naturally occurring inhibitors are also able to inhibit MMPs and other proteases. Alpha 2-macroglobulin is the most prominent occurring circulating protease inhibitor but due to its large size its effectiveness as an inhibitor in areas of wound healing after infarction may be limited.
4.4. MMPs post-myocardial infarction
Collagenase (MMP-1) was demonstrated in the normal myocardium, where it could be located in the interstitium, in the neighborhood of its substrate,
fibrillar collagen [36]. Myocardial MMPs are produced by fibroblast-like cells inflammatory cells as well as by cardiomyocytes, and are predominantly present in their latent form. MMPs are increasingly expressed and activated in several pathological conditions of the heart [37-41]. Increased MMP-1, -2, -3 and -9 expression and activity was demonstrated in infarcted rat and porcine hearts [21, 42-45]. Differences in the time course of post-infarction myocardial MMP activity have been demonstrated but most authors agree that MMP activation starts early, within one day post-infarction. This is most probably due to the influx of inflammatory cells, e.g. granulocytes, which need active MMPs (e.g., MMP-9) to invade the infarcted ventricle. TIMPs are normally in delicate balance with the MMP activity, but loss of TIMP-mediated inhibitory control has also been reported to occur in several cardiac pathologies [39, 40, 46].
4.5. Pharmacological inhibition
During wound healing, including wound healing post-myocardial infarction, extracellular matrix turnover is one of the essential processes which occurs. Proteolytic degradation of the extracellular matrix takes place at different levels: 1) degradation of pre-existing extracellular matrix components, 2) promoting cell migration during inflammation, angiogenesis and granulation tissue formation, 3) remodeling of synthesized extracellular matrix in for example, scar tissue and 4) regulation of growth factors (e.g. and by proteolytic release and activation [20]. Activation of MMPs after infarction might result in collagen degradation and progressive ventricular dilatation [47]. Chronic treatment with MMP inhibitors after infarction might have a beneficial effect on long-term left ventricular remodeling by increasing collagen deposition, decreased LV dilatation and increased cardiac function. The synthetic MMP inhibitors used belong to the hydroxamate class or are chemically modified tetracyclines. One of the greatest problems of the hydroxamic acid-based MMP inhibitors is the poor oral bioavailability and toxicity [48]. In a porcine study of 3 weeks rapid pacing, MMP inhibition limits LV remodeling and reduces wall stress [49].
In a mouse myocardial infarction study a broad range MMP inhibitor attenuates left ventricular dilatation 4 days after infarction [50]. A selective MMP inhibitor that does not inhibit MMP-1 was used in a rabbit model of myocardial infarction. At 4 weeks after MI, there were no differences between untreated and treated animals in infarct size or collagen deposition but the MMP inhibitor attenuated ventricular dilation, reduced infarct wall thinning and increased neovascularization in the subendocardium [51]. Treatment of mouse infarcts for 1 or 2 weeks with the MMP inhibitor GM6001 (Galardin, Ilomastat) delayed wound healing. After 1 week of treatment attenuation of left ventricular dilatation and thinning and reduction of collagen deposition in the infarct was
observed [52]. The thicker infarcts might be explained by preservation of the pre-existing extracellular matrix, which inhibits myocyte slippage. The larger necrotic areas observed after 1 week of MMP inhibition, the reduction of cell numbers and the reduced collagen deposition may seem a paradox to MMP inhibition, but inflammatory cells including granulocytes and macrophages responsible for the removal of the necrotic debris and the influx of myofibroblasts responsible for collagen production need MMPs to migrate towards the area of infarction. By the use of MMP inhibitors both inflammatory cell and myofibroblast influx, and therefore debris removal and collagen deposition are transiently impeded. MMP inhibition might also interfere with the release and activation of growth factors and cytokines, like and IL-1, which will in turn also influence the remodeling process after infarction [20, 53]. Decreased activity of might reduce the synthesis of new collagen fibers [54].
5. Genetically Modified Animal Studies
The plasminogen-plasmin system is not only involved in fibrinolysis but is also a key regulatory system for MMP activity in the heart. Plasmin, a serine protease, is the active enzyme of the plasminogen (Plg) system and degrades a variety of ECM components [55]. The generation of plasmin is primarily controlled by the balance between the plasminogen activators (tPA and uPA) and their physiological inhibitors, the plasminogen activator inhibitors (PAIs).
Inhibition of wound healing after infarction even 5 weeks after myocardial infarction was observed in urokinase plasminogen activator uPA-deficient [35]
and plasminogen Plg-deficient [56] mice but not in tissue type plasminogen activator tPA-deficient mice. Others also described a plasmin-independent activation pathway of MMP activation [57-59]. These findings suggest a central role for the uPA-mediated plasminogen-plasmin system in cardiac wound healing after myocardial infarction in mice. Three distinct observations strongly suggest that the effects of plasminogen and uPA deficiency are mediated by reduced activation of MMPs. First, uPA was coexpressed with MMP-9 in infiltrating leukocytes [35]. Second, MMP activity was reduced in both uPA-/- and Plg-/- infarcts. Third, MMP inhibition by pharmacological tools has comparable, although less pronounced, effects on infarct healing and cardiac rupture as uPA/plasminogen deficiency.
Cardiac rupture was also inhibited in the uPA-deficient and MMP-9 deficient mice and in mice treated after infarction with adenovirus mediated TIMP-1 or plasminogen activator inhibitor-1 (PAI-1) gene transfer but not in MMP-2 or MMP-12 deficient mice. These data suggest that uPA and MMP-9 activity predispose to cardiac rupture, whereas increased levels of PAI-1 and TIMP-1 may be protective [35]. Prevention of cardiac rupture by local TIMP-1
or PAI-1 overexpression may thus, be developed as a non-surgical treatment.
As already demonstrated in the study of Heymans et al. [35], MMP-9 plays a crucial role in the influx of inflammatory cells in the early phase of the wound healing. The significance of MMP-9 activity in early infarct healing and rupture was emphasized by the observation that MMP-9 was predominantly found in leukocytes and macrophages and that its activity peaked around day 2, the period in which most of the ruptures occur. This indicates that by degrading matrix molecules, MMP-9 allows inflammatory cells to infiltrate the infarct and to disrupt the collagen network, a prerequisite for cardiac rupture [60].
Furthermore, targeted deletion of MMP-9 attenuated LV dilatation as well, at 15 days post-MI [61]. Limited LV dilatation was accompanied with a reduced inflammatory response and a decrease in collagen deposition in the infarct of MMP-9 deficient mice [62]. Interestingly, these MMP-9 null mice had increased expression of MMP-3 and MMP-13 in ventricular tissue compared to the wild-types. This indicates that compensatory upregulation of other MMPs with possible overlapping MMP substrates should be taken into consideration when interpreting MMP deletion experiments [63].
6. Future Directions
It is still a matter of debate whether a stiffer scar is more beneficial than a more compliant scar. Therefore, the timing of treatment should be a topic of future research in order to determine whether interfering with extracellular matrix remodeling should be started either immediately after infarction or later on. In some of the described animal studies MMP inhibitor administration started before the onset of infarction. Therefore the effect might be smaller when the inhibitors are given after infarction. Inhibition of MMP activity might be a new therapeutic concept to retard development of heart failure and cardiac dysfunction but long term effects have not yet been established.
The positive effects of MMP inhibition on LV dilatation in animal models led to the proposal to use MMP inhibitors as a potential therapy for patients at risk for the development of heart failure after MI. Although the promising results in animal studies encourage the design of clinical trails with MMP inhibitors, several issues have to be studied more extensively. First, the precise effect of MMP inhibitor treatment on cardiac function has to be studied more extensively. Second, the timing of MMP inhibitor administration after infarction has to be resolved and third, the choice between narrow versus broad range MMP inhibitors has to be made.
Another important issue is which type of MMP inhibitors should be used, broad range MMP inhibitors or inhibitors with a selective specificity?
Broad range MMP inhibitors could be maximally effective, but could also induce negative side effects and might effect normal tissue as well. The use of
selective MMP inhibitors could be favorable in some processes after infarction but the wound healing after infarction is orchestrated by numerous MMPs, each of them having specific tasks, which might be taken over by other less specific MMPs when they are specifically inhibited. When a selection of MMP inhibitors is to be made, inhibition of MMP-9 may be a suitable candidate, since the targeted deletion of MMP-9 attenuates left ventricular enlargement and collagen content after infarction [61] and decreases the influx of leukocytes and the incidence of cardiac rupture [35].
Regulating the balance of extracellular matrix remodeling either by extracellular matrix synthesis or degradation is a possible mechanism to prevent heart failure after infarction. MMP inhibitors might serve in the future as new therapeutic strategies for heart failure.
Besides regulation of extracellular matrix remodeling, restoring the contractile behavior of the infarcted area could beneficial for the treatment of heart failure. Recent studies described that infused bone marrow derived angioblasts or implanted adult stem cells in the infarcted heart reduce remodeling and improve cardiac f u n c t i o n by promoting vasculogenesis/angiogenesis and regeneration of ischemic cardiac muscle [64- 66]. On the other hand stimulation of differentiation to myofibroblasts and prevention of myofibroblast loss might be another new therapeutic strategy to generate a more functional scar tissue post-infarction. Although these new techniques have to deal with a lot of pitfalls, such as the access and selection of these cells and silencing the immune system, they represent potential promising new heart failure treatments.
Acknowledgements
Supported by grants of the Netherlands Heart Foundation (NHS 94.012 and NHS 99.054) and the Netherlands Organization for Scientific Research (NWO 902-16-098).
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