Matrix Metalloproteinase Inhibition After Myocardial Infarction

Abstract

Abstract-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. Key Words: myocardial infarction Ⅲ therapy Ⅲ matrix metalloproteinase inhibition M yocardial infarction (MI) leads to complex architectural alterations involving both the infarcted and noninfarcted myocardium. Dilatation of the left ventricle and infarct thinning, also called infarct expansion, are the most prominent structural changes in the infarct region. 1 Patients exhibiting extensive infarct expansion after MI are more likely to experience complications, such as the development of congestive heart failure, aneurysm formation, and myocardial rupture. 2 The extent of ventricular dilatation after MI is related to several factors such as the magnitude of the initial Original

Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed

“…However, it is uncertain whether calcification is a marker for plaque instability [26]. Recent studies showing that pharmacological inhibition of MMPs attenuates ventricular dilation, increases collagen content, and stabilizes atherosclerotic plaque, lead us to speculate that TIMP-1, a natural inhibitor of MMPs, could well provide protection against plaque instability [13,27,28]. The observed correlation between TIMP-1 and increased type I collagen would also support a role for this inhibitor in the maintenance of vascular integrity.…”

Matrix metalloproteinases in cardiovascular disease

“…This has indeed been borne out with basic proof of concept studies (20), particularly with the inhibition of MMP-9, one of the major gelatinases involved in postinfarct remodelling (21,22). Most of these studies demonstrate a reduction in ventricular size and improvement in ventricular function with administration of the MMP inhibitors (23)(24)(25). Unfortunately, a number of leading candidates have been withdrawn from active development for this indication because of fibromyalgia side effects in earlier trials attempting to decrease metastasis in cancer.…”

Differential Regulation of Matrix Metalloproteinase-2 and -9 Expression and Activity in Adult Rat Cardiac Fibroblasts in Response to Interleukin-1β

“…Matrix metalloproteinases (MMPs), 1 a family of endopeptidases, have the ability to degrade extracellular matrix proteins, and therefore, play a fundamental role in tissue remodeling (1)(2)(3)(4)(5)(6). MMPs are implicated in the remodeling processes of the heart during chronic heart failure and following myocardial infarction (6 -10).…”