Matrix Metalloproteinases: From Biology to Therapeutic Strategies in Cardiovascular Disease

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Abstract
Recent decades have witnessed substantial strides in our efforts to reduce both morbidity and mortality resulting from congenital and acquired forms of heart disease.1Traditional therapies using inotropic agents (eg, digoxin) for congestive heart failure (CHF) are now surpassed in efficacy by new classes of pharmacologic agents, such as angiotensin-converting enzyme (ACE) inhibitors, which exert both central (eg, myocardial remodeling) and peripheral (eg, afterload reduction) effects. New insights about the etiologic factors and progression of CHF have emerged from the mechanisms that mediate the physiologic roles of ACE inhibitors at the cellular level. At the same time, the emphasis has shifted away from the cardiomyocyte per se to consider the physiologic role of the connective tissue elements and matrix remodeling, within the extracellular milieu, in the pathophysiology of heart failure. Matrix metalloproteinases (MMPs), a large multigene class of endopeptidases, are rapidly emerging as the next molecular targets whose biologic roles are involved in a wide spectrum of human pathologies. MMP distribution in the organism reflect the scope of the clinical burden, spanning entities such as degenerative rheumatoid arthritis, cancer metastasis, periodontitis, renal disease, and certain cardiac and vascular diseases. Evidence, which is ever accumulating, suggests that MMPs and their endogenous tissue inhibitors (TIMPs) are possible targets for future therapeutic strategies in cardiovascular diseases. Both challenges and opportunities exist to reduce restenosis after angioplasty, to increase graft potency after coronary artery bypass, and to improve the survival of inheritable disorders, such as hypertrophic cardiomyopathy and Marfan syndrome. Hence, the primary goals in this review are to demystify the extracellular matrix (ECM), to provide a bench-to-bedside overview of the basic foundations in this burgeoning field, and to lay out a conceptual framework for the clinician to consider new therapeutic strategies on the horizon targeted to interactions between MMPs and TIMPs in …