Current Topics in Medicinal Chemistry - Volume 12, Issue 10, 2012

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The family of matrix metalloproteinases (MMPs) comprises 24 multidomain enzymes with a zinc-dependent activity. Their structural diversity over the archetypal domain organization confers variable biological function to these molecules ranging from cellular homeostasis and control of tissue turnover to implication in multiple pathological conditions such as inflammation, arthritis, cardiovascular disease and cancer. MMP expression and activity exhibits high tissuespecies- and signal-specificity and involves multiple regulatory mechanisms that co-ordinate zymogen activation, endogenous inhibition and gene transcription. In this article, we provide an overview of the molecular mechanisms that regulate MMPs gene expression at transcriptional and post-transcriptional level through integration of signals from multiple pathways to cis-acting elements present in MMP promoters, epigenetic modifications, mRNA stability mechanisms and microRNA modulation. Loss of MMP activity through mutations and single nucleotide polymorphisms is further discussed in the context of disease susceptibility.

Metalloproteinases (MMPs) are enzymes which enhance proteolysis of extracellular matrix proteins. The pathophysiologic and prognostic role of MMPs has been demonstrated in numerous studies. The present review covers a wide a range of topics with regards to MMPs structural and functional properties, as well as their role in myocardial remodeling in several cardiovascular diseases. Moreover, the clinical and therapeutic implications from their assessment are highlighted.

Inflammatory process is essential for the initiation and progression of vascular remodeling, entailing degradation and reorganization of the extra-cellular matrix (ECM) scaffold of the vessel wall, leading to the development of atherosclerotic lesions. Matrix metalloproteinases (MMPs) are zing dependent endo-peptidases found in most living organisms and act mainly by degrading ECM components. Most MMPs are formed as inactive proenzymes and are activated by proteolysis. This process depends and is regulated by other proteases and endogenous MMP inhibitors (TIMPs). MMPs and TIMPs play a major role not only in ECM degradation but also in mediating cell migration, proliferation, tissue remodeling; acting as a signal for the production and secretion of growth factors and cytokines. More importantly MMPs through proteolysis and degradation of ECM contribute in many physiological and pathological processes including organ development, wound healing, tissue support, vascular remodeling and restenosis, atherosclerosis progression, acute coronary syndromes, myocardial infarction, cardiomyopathy, aneurysms remodeling, cancer, arthritis, and chronic inflammatory diseases. A substantial body of evidence support the notion that imbalance between the activity of MMPs and their tissue inhibitors (TIMPs) contribute to the pathogenesis of cardiovascular diseases such as atherosclerosis, vascular remodeling and progression of heart failure. In this review, we will discuss the relationship between MMPs, inflammation and atherosclerosis under the topic of cardiovascular disease.

The matrix metalloproteinases/tissue inhibitors of metalloproteinases system is involved in the regulation of extracellular matrix metabolism, which plays a crucial role with regards to maintenance of tissue integrity. During the occurrence of vascular pathologies including hypertension, the balance between proteases and their inhibitors is temporally destroyed. Even though there are conflicting data in the literature regarding the expression pattern of the vascular matrix metalloproteinase system, the occurring extracellular matrix turnover leads to the change of arterial mechanical properties. For example, hypertension plays crucial role in the formation of cardiovascular remodeling which seems to be characterized by an increase in extracellular matrix. Changes in arterial stiffness, a predictor for cardiovascular morbidity and mortality, are determined by alterations in vascular extracellular matrix due to hemodynamic, genetic, or other factors. It has become increasingly evident that blockade of the renin-angiotensin-aldosterone system and other pharmacological strategies, seem to be particularly effective in reducing vascular stiffness and collagen content in human and animal models. However, the relationship between extracellular matrix metabolism and the effects of therapy in hypertensive patients needs to be further explored in larger trials over a longer period of time.

Diabetes mellitus (DM) is a leading risk factor for cardiovascular disease that adversely affects multiple vascular components from early in its course. Current evidence implicates matrix metalloproteinases (MMPs) and their endogenous inhibitors in diverse pathways associated with the development and progression of diabetic microvascular complications. In diabetic nephropathy, altered MMPs expression contributes to extracellular matrix deposition and glomerular hypertrophy that eventually lead to proteinuria and renal insufficiency. In diabetic cardiomyopathy, MMPs participate in the breakdown of collagen and elastin, myocardial remodelling as well as the vulnerability of the coronary plaque. The development of diabetic peripheral arterial disease is mediated by the impaired angiogenesis caused by the activity of MMPs. Experimental data support an integral role of MMPs in cerebral circulation and stroke volume in diabetes. An excess of MMPs may contribute in poor diabetic wound healing. Future research should further clarify the role of MMPs within the pathophysiological substrate of diabetes, as well as potential therapeutic options.

Atherosclerotic coronary artery disease, the underlying basis for ischemic heart disease, is the leading cause of death and disability in the USA and recent trends indicate that coronary artery disease is also becoming a major public health problem in developing countries [1]. Atherosclerosis is a continuous process that is initiated early in life, which gradually progresses with potentially devastating consequences: atherosclerotic plaque rupture is the most common underlying pathological mechanism creating acute ischemic coronary syndromes [2]. This term refers to the process of disruption of the endothelial surface and the exposure of the underlying prothrombotic vessel wall to circulating platelets and coagulation factors. In order to identify the high-risk plaque we need to recognize its specific morphological and functional characteristics. The morphological characteristics have been identified in several human histopathological and in vivo studies, and include: 1) a large lipid core (≥40% plaque volume) composed of free cholesterol crystals, cholesterol esters, and oxidized lipids impregnated with tissue factor, 2) a thin fibrous cap depleted of smooth muscle cells and collagen, 3) an outward (positive) remodeling, 4) inflammatory cell infiltration of fibrous cap and adventitia (mostly monocyte- macrophages, activated T cells and mast cells), and 5) increased neovascularization. The terms vulnerable, unstable or ‘high-risk’ are now widely used to describe plaques that exhibit such features, irrespective of whether rupture of the fibrous cap is present [3].

Heart failure (HF) represents a complex multifactorial syndrome, characterized by crucial structural and functional abnormalities of the myocardium. Matrix metalloproteinases are associated with left ventricular dysfunction, adverse left ventricular remodelling and prognosis after acute myocardial infarction. There is a strong association between oxidative stress and MMPs in the pathophysiology of HF. As MMPs are strongly associated to the pathogenesis and pathophysiology of HF, several agents have been proposed as potential modulators of these molecules. Classical agents such as statins, angiotensin converting enzyme inhibitors (ACEIS) and beta-blockers and a variety of novel agents have been implicated in the pathogenesis and progression of heart failure via the matrix metalloproteinases pathway and consist of possible future therapeutic targets.

Matrix metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells and are responsible for much of the turnover of matrix components. Several studies have shown that MMPs are involved in all stages of the atherosclerotic process, from the initial lesion to plaque rupture. Recent evidence suggests thatMMP activity may facilitate atherosclerosis, plaque destabilization, and platelet aggregation. In the heart, matrix metalloproteinases participate in vascular remodeling, plaque instability, and ventricular remodelling after cardiac injury. The aim of the present article is to review the structure, function, regulation of MMPs and to discuss their potential role in the pathogenesis of acute coronary syndromes, as well as their contribution and usefullness in the setting of the disease.

It is well established that matrix metalloproteinases (MMPs) contribute to the degradation of the extracellular matrix of coronary plaque and contribute to the thinning of the fibrous cap. As a result, the atheromatous plaque becomes unstable and prone to rupture with consequent clinical manifestations including acute coronary syndromes. Moreover, genetic polymorphisms of MMPs have been found to be associated with the concentration of circulating MMPs, and over the past decade, considerable efforts have been devoted to explore the relationships between MMPs polymorphisms and myocardial infarction risk among various populations. However, existing studies have yielded inconsistent results. Some observations have suggested that genetic variation that affects the expression of MMPs may contribute to the occurrence of myocardial infarction, whereas others reported no support for an association of MMPs polymorphisms with myocardial infarction susceptibility. Furthermore, the interpretation of these studies has been complicated by the use of different populations or different control sources. Therefore, further studies are required to evaluate the role of matrix metalloproteinases and especially the associated genetic polymorphisms in cardiovascular disease.

Matrix metalloproteinases (MMPs), are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in atherosclerotic plaque development, coronary artery disease and heart failure. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression, MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review discusses pharmacological approaches to MMP inhibition.