Mechanisms of extracellular matrix remodeling in dilated cardiomyopathy

BACKGROUND: The mechanisms underlying myocardial remodeling during heart failure have historically been attributed as the consequence of intrinsic changes in cardiac myocytes. Nevertheless, over the last several years, it has become increasingly evident that disruption of extracellular matrix (ECM) homeostasis is also a deciding factor for the progression of myocardial failure. PATHOGENETIC MECHANISMS: Collagens, the chief components of extracellular matrix, are a tightly regulated family of proteins that determine the structural and functional integrity of heart. Synthesis of collagens is regulated at the cellular level while deposition of these proteins depend on a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). Infiltrating inflammatory cells are major producers of MMPs though myocardial cells are also found to synthesize these proteolytic enzymes. However, immune-mediated regulation of myocardial collagen synthesis and deposition during myocardial inflammation remains poorly understood. It seems likely that a paracrine/autorine effect of a repertoire of cytokines on inflammatory cells and myocardial cells may lead to an imbalance in myocardial MMP/TIMP ratio resulting, eventually, in altered myocardial extracellular matrix architecture and contribute significantly to the development of left ventricular remodeling and dysfunction. CONCLUSION: Attempts to delineate the cross-talk between immune cells, myocardial cells and extracellular matrix are important as chronic myocardial inflammation is documented in about 50% of patients with dilated cardiomyopathy.     

Immunomodulation and matrix metalloproteinases in viral myocarditis

Myocarditis is an inflammatory disorder induced most commonly by infectious agents. The natural course of the disease is broad and ranges from complete recovery to dilated cardiomyopathy and death. The mechanisms of the incomplete recovery remain poorly understood but extracellular matrix remodelling by metalloproteinases seems to be important for the progression to dilated cardiomyopathy and chronic heart failure. The matrix metalloproteinases (MMPs) are proteolytic enzymes whose role was thought to be the degradation of matrix components only. In the last few years a considerable amount of evidence has gathered which shows new functions of the MMPs as powerful modulatory factors in inflammatory disorders. MMPs facilitate the migration of immune cells through the basement membrane, process cytokines and chemokines by modulating their function, and regulate the relationship of cells with ECM components. These findings enhance our knowledge of the role of MMPs in viral myocarditis and inflammatory cardiomyopathy and may lead to a new understanding which might allow for specific and successful therapeutic interventions in the future.     

Targeting Matrix Metalloproteinase Activity and Expression for the Treatment of Viral Myocarditis

Infectious agents including viruses can infect the heart muscle, resulting in the development of heart inflammation called myocarditis. Chronic myocarditis can lead to dilated cardiomyopathy (DCM). DCM develops from the extensive extracellular matrix (ECM) remodeling caused by myocarditis and may result in heart failure. Epidemiological data for viral myocarditis has long suggested a worse pathology in males, with more recent data demonstrating sex-dependent pathogenesis in DCM as well. Matrix metalloproteinases (MMPs), long known modulators of the extracellular matrix, have important roles in mediating heart inflammation and remodeling during disease and in convalescence. This ability of MMPs to control both the inflammatory response and ECM remodeling during myocarditis makes them potential drug targets. In this review, we analyze the role of MMPs in mediating myocarditis/DCM disease progression, their sex-dependent expression, and their potential as drug targets during viral myocarditis and DCM.     

Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target

A fundamental structural event in the progression of heart failure due to dilated cardiomyopathy is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) are an endogenous family of enzymes which contribute to matrix remodeling in several disease states. The goal of this report is to summarize recent findings regarding the myocardial MMP system and the relation to matrix remodeling in the failing heart. In both experimental and clinical forms of dilated cardiomyopathy (DCM), increased expression of certain species of myocardial MMPs have been demonstrated. Specifically, increased myocardial levels of the gelatinase, MMP-9 has been identified in both ischemic and non-ischemic forms of human DCM. In addition, stromelysin or MMP-3 increased by over four-fold in DCM. The increased levels of MMP-3 in DCM may have particular importance since this MMP degrades a wide range of extracellular proteins and can activate other MMPs. In normal human LV myocardium, the membrane type 1 MMP (MT1-MMP) was detected. These MT-MMPs may provide important sites for local MMP activation within the myocardium. In a pacing model of LV failure, MMP expression and activity increased early and were temporally associated with LV myocardial matrix remodeling. Using a broad-spectrum pharmacological MMP inhibitor in this pacing model, the degree of LV dilation was attenuated and associated with an improvement in LV pump function. Thus, increased LV myocardial MMP expression and activity are contributory factors in the LV remodeling process in cardiomyopathic disease states. Regulation of myocardial MMP expression and activity may be an important therapeutic target for controlling myocardial matrix remodeling in the setting of developing heart failure.     

Matrix metalloproteinases: regulation and dysregulation in the failing heart

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for myocardial extracellular protein degradation. Several MMP species identified within the human myocardium may be dysregulated in congestive heart failure (CHF). For example, MMPs that are expressed at very low levels in normal myocardium, such as collagenase-3 (MMP-13) and the membrane-type-1 MMPs, are substantially upregulated in CHF. However, MMP species are not uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio of MMPs are expressed in the failing myocardium. With the use of animal models of CHF, a mechanistic relationship has been demonstrated with respect to myocardial MMP expression and the left ventricular (LV) remodeling process. The tissue inhibitors of the MMPs (TIMPs) are locally synthesized proteins that bind to active MMPs and thereby regulate net proteolytic activity. However, there does not appear to be a concomitant increase in myocardial TIMPs during the LV remodeling process and progression to CHF. This disparity between MMP and TIMP levels favors a persistent MMP activation state within the myocardium and likely contributes to the LV remodeling process in the setting of developing CHF. The elucidation of upstream signaling mechanisms that contribute to the selective induction of MMP species within the myocardium as well as strategies to normalize the balance between MMPs and TIMPs may yield some therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process.     

Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction

OBJECTIVE: Myocardial collagen degradation is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). The possible relevance of MMPs in association with the inflammatory induction was investigated in a murine coxsackievirus B3 myocarditis model. METHODS: Hearts from viral infected and sham-infected BALB/c mice were analyzed by semi-quantitative RT-PCR, picrosirius red staining, Western blot analysis, and immunohistochemistry. RESULTS: In viral infected mice, both mRNA and protein abundance for collagen type I remained unaltered. In addition, picrosirius red staining showed the unchanged total collagen content. However, degraded soluble fraction of collagen type I protein was increased. Moreover, the mRNA abundance for MMP-3 and MMP-9 was upregulated, whereas the mRNAs for TIMP-1 and TIMP-4 were downregulated, respectively. The upregulation of MMP-3/MMP-9 and downregulation of TIMP-4 were confirmed at the protein level, and were associated with significantly increased mRNA levels of interleukin 1beta, tumor necrosis factor-alpha, transforming growth factor-beta1 and interleukin-4. CONCLUSION: The increment of MMPs in the absence of counterbalance by TIMPs may lead to a functional defect of the myocardial collagen network by posttranslational mechanisms. This may contribute significantly to the development of left ventricular dysfunction in murine viral myocarditis. The inflammatory response with induction of cytokines may mediate the dysregulation of the myocardial MMP/TIMP systems.     

Role of matrix metalloproteinases in asthma

Airway inflammation and remodeling are key features of asthma. Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) are thought to contribute to the pathogenesis of asthma via their influence on the function and migration of inflammatory cells as well as matrix deposition and degradation. TIMPs bind MMPs in a 1:1 fashion. Thus, an increase in the molar ratio of MMP/TIMP may favor tissue injury, while the reverse could be associated with increased fibrosis. MMP-9 is the predominant MMP in asthma, and its expression is enhanced when patients have spontaneous exacerbations or in response to local instillation of allergen in the airway. As acute inflammation resolves, MMP-9 levels return toward normal. Interestingly, corticosteroids downregulate MMP and enhance TIMPs. Even though it is clear that enhanced airway inflammation in asthma is associated with increased expression of MMPs, whether specific inhibitors of MMP could reduce airway injury and facilitate orderly healing in asthma is still unknown.     

Synergic and antagonistic relationship between MMP‐2 and MMP‐9 with fibrosis and inflammation in Chagas' cardiomyopathy

Cardiomyopathy is the most important clinical manifestation in the chronic phase of Chagas' disease because of its frequency, severity and impact on morbidity and mortality. The extracellular matrix degradation during cardiac remodeling in Trypanosoma cruzi infection is driven by matrix metalloproteinases (MMPs), primarily the MMP‐2 and MMP‐9 gelatinases. MMPs also regulate some molecules related to inflammation, such as growth factors, cytokines and chemokines. The involvement of MMP‐2 and MMP‐9 is not yet fully understood in Chagas' disease. It has been proposed that the gelatinases may have opposite effect on inflammation/regulation and cardiac remodeling. MMP‐2 would participate in regulation, offering a protective role for cardiac damage in asymptomatic patients and would be a good marker for the initiation of changes in the heart. On the other hand, MMP‐9 can be used as a marker for serious changes on the heart and would be associated with inflammation and fibrosis. Here, we consolidate all characteristics involving MMP‐2 and MMP‐9 in Chagas' disease based on current studies to clarify their participation on the inflammation/regulation and fibrosis, and the synergistic or antagonistic role between them.     

Dilated Cardiomyopathies as a Cause of Congestive Heart Failure

DEFINITION AND CLASSIFICATION: Cardiomyopathies are disorders affecting the heart muscle that frequently result in congestive heart failure. Five major forms are recognized: dilated, hypertrophic, restrictive, right ventricular, and nonclassifiable cardiomyopathies with distinct hemodynamic properties. Furthermore, the new WHO/WHF definition also comprises inflammatory cardiomyopathy, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm2), the term viral cardiomyopathy or viral persistence in dilated cardiomyopathy should be applied. DIAGNOSIS AND TREATMENT: In recent years, there have been breakthroughs in understanding the molecular and genetic mechanisms involved in this group of conditions, enabling improvement of diagnostic strategies and introduction of new therapies. Ongoing evaluation of antiviral, immunoglobulin, and immunosuppressive therapies including the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID), removal of antibodies by immunoadsorption, anticytokine and gene therapy, as well as the mechanical support devices may provide new treatment options.     

Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?

Increased activity of matrix metalloproteinases (MMPs) has been implicated in numerous disease processes, including tumor growth and metastasis, arthritis, and periodontal disease. It is now becoming increasingly clear that extracellular matrix degradation by MMPs is also involved in the pathogenesis of cardiovascular disease, including atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction. Administration of synthetic MMP inhibitors in experimental animal models of these cardiovascular diseases significantly inhibits the progression of, respectively, atherosclerotic lesion formation, neointima formation, left ventricular remodeling, pump dysfunction, and infarct healing. This review focuses on the role of MMPs in cardiovascular disease, in particular myocardial infarction and the subsequent progression to heart failure. MMPs, which are present in the myocardium and capable of degrading all the matrix components of the heart, are the driving force behind myocardial matrix remodeling. The recent finding that acute pharmacological inhibition of MMPs or deficiency in MMP-9 attenuates left ventricular dilatation in the infarcted mouse heart led to the proposal that MMP inhibitors could be used as a potential therapy for patients at risk for the development of heart failure after myocardial infarction. Although these promising results encourage the design of clinical trials with MMP inhibitors, there are still several unresolved issues. This review describes the biology of MMPs and discusses new insights into the role of MMPs in several cardiovascular diseases. Attention will be paid to the central role of the plasminogen system as an important activator of MMPs in the remodeling process after myocardial infarction. Finally, we speculate on the use of MMP inhibitors as potential therapy for heart failure.     

基质金属蛋白酶及其组织抑制剂与病毒性心肌炎心肌纤维化

心肌纤维化是病毒性心肌炎向扩张型心肌病转化的重要环节,由心肌胶原代谢失衡引起,近年来基质金属蛋白酶及其组织抑制因子(MMPs/TIMPs)这一胶原降解系统比例失调造成病毒性心肌炎中胶原合成降解代谢紊乱并导致心肌发生纤维化。     

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.     

Association of matrix metalloproteinase expression and left ventricular function in idiopathic dilated cardiomyopathy

Myocardial remodeling is an important predictor for the development of dilated cardiomyopathy (DCM). Matrix metalloproteinases (MMPs) are the family of proteins responsible for extracellular remodeling, and tissue inhibitors of metalloproteinases (TIMPs) tightly control their activity. In the present study, the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 was determined by immunohistochemistry in right ventricular endomyocardial biopsy samples from 16 patients with idiopathic DCM, and its clinical significance was evaluated by comparison with parameters of cardiac function. To obtain a semi-quantitative assessment of MMP and TIMP expression, the average number of positive cells per high power field was counted. The left ventricular ejection fraction (LVEF) significantly correlated with the expression of both MMP-2 (r=-0.68) and TIMP-2 (r=-0.58). Patients were classified into 2 groups according to the degree of MMP-2 expression: strongly positive and weakly positive. LVEF, left ventricular (LV) end-diastolic pressure, right ventricular end-diastolic pressure, pulmonary capillary wedge pressure and the plasma norepinephrine level were significantly greater in the strongly positive group (p<0.05). In conclusion, the expression of MMPs and TIMPs in the cardiac matrix of patients with idiopathic DCM is closely associated with myocardial remodeling and subsequent deterioration of LV performance. These findings suggest new therapeutic targets for patients with idiopathic DCM.     

Novel approaches to retard ventricular remodeling in heart failure

While the etiologies of congestive heart failure (CHF) are diverse, a common event in the progression of this disease process is LV remodeling, increased wall stress, and subsequent pump dysfunction. Therapeutic approaches for CHF have been focused upon reducing LV afterload through vasodilator therapy, or by blocking/interrupting the effects of neurohormonal stimuli. However, another therapeutic approach would be to directly intervene in the LV remodeling process with CHF. An important determinant in the maintenance of myocyte shape, alignment and transduction of myocyte shortening into an overall ejection is the structural support provided by the fibrillar collagen matrix. As in most tissue remodeling processes, LV myocardial remodeling with CHF is accompanied by changes in the structure and composition of the collagen matrix. Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which have been identified to be responsible for matrix remodeling and alterations in MMP expression and activity have been identified in clinical and animal models of CHF. Moreover, alterations in the tissue inhibitors of MMPs (TIMPs) have also been identified to occur in the end-stage CHF myocardium. Thus, it is very likely that increased MMP activity and reduced inhibitory control of the TIMPs contribute to the LV remodeling process with CHF. A number of bioactive peptides and cytokines influence MMP and TIMP expression and activity. In addition, pharmacologically active MMP inhibitors have been synthesized and are currently under study. Accordingly, the control of MMP and TIMP expression and activity within the failing myocardium represents a new and potentially significant therapeutic target for CHF.     

Temporal and Spatial Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Following Myocardial Infarction

Following a myocardial infarction (MI), the homeostatic balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is disrupted as part of the left ventricle (LV) response to injury. The full complement of responses to MI has been termed LV remodeling and includes changes in LV size, shape and function. The following events encompass the LV response to MI: (1) inflammation and LV wall thinning and dilation, (2) infarct expansion and necrotic myocyte resorption, (3) accumulation of fibroblasts and scar formation, and (4) endothelial cell activation and neovascularization. In this review, we will summarize MMP and TIMP roles during these events, focusing on the spatiotemporal localization and MMP and TIMP effects on cellular and tissue‐level responses. We will review MMP and TIMP structure and function, and discuss specific MMP roles during both the acute and chronic phases post‐MI, which may provide insight into novel therapeutic targets to limit adverse remodeling in the MI setting.     

基质金属蛋白酶/基质金属蛋白酶组织抑制剂与心房颤动

基质金属蛋白酶是一个细胞外基质降解酶家族,基质金属蛋白酶组织抑制剂是其内源性抑制物.二者平衡在细胞外基质合成及降解过程中起重要作用,与心房颤动过程中心房结构重塑,即心房纤维化及心房扩大相关.目前研究显示基质金属蛋白酶/基质金属蛋白酶组织抑制剂失衡与心房颤动的发生、发展及复发相关,抑制基质金属蛋白酶可改善心房重塑并阻止心房颤动进展.恢复基质金属蛋白酶/基质金属蛋白酶组织抑制剂平衡可能成为治疗心房颤动的新型治疗途径.     

Matrix Metalloproteinases: Pathways of Induction by Bioactive Molecules

Regulation of the extracellular matrix (ECM) is an important therapeutic target that can potentially attenuate the adverse ventricular remodeling seen in the progression of heart failure. Matrix metalloproteinases (MMPs) degrade numerous ECM proteins. Importantly, the activation of MMPs and their endogenous inhibitors (TIMPs) are associated with ventricular remodeling. Bioactive-molecules (vasoactive peptides) become activated in proportion to the magnitude of heart failure and have been demonstrated to affect directly collagen degradation as well as collagen synthesis in the myocardium. Pro-fibrotic factors such as norepinephrine, angiotensin II, and endothelin-1 stimulate fibrosis by modulating collagen synthesis and MMP/TIMP activity. Antagonism of these bioactive-molecules has produced improved hemodynamic performance concomitant with modulation of MMP/TIMP activity and in association with reverse remodeling. The natriuretic peptides and nitric oxide, both of which function via the second messenger cGMP, demonstrate anti-fibrotic actions by inhibiting collagen synthesis and by stimulating MMP activity. Furthermore, bioactive-molecules along with certain cytokines are reported to amplify MMP activity, suggesting that different signaling systems work together to modulate ECM turnover. Taken together, the evidence supports an important functional role for bioactive-molecules in the regulation of ECM turnover and suggests that pharmacological intervention at the level of such bioactive molecules may provide potential therapeutic strategies for attenuation of the adverse ventricular remodeling associated with the progression of heart failure.