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The effects of vitronectin at sites of myocardial ischemia and infarction Walinski, Hubert Paul

Abstract

Myocardial infarction (MI) results from the thrombotic occlusion of an atherosclerotic coronary artery in patients with ischemic heart disease. The plasminogen activator (PA)/plasmin system plays significant roles in events leading to wound healing following MI. Vitronectin (VN) is an acute phase plasma protein which has a direct influence over the constituents of the plasminogen activator/plasmin system. However, the effects of VN on cardiac function and wound healing following ischemia and infarction remain to be elucidated. My dissertation addresses the investigation of the specific role of VN at sites of myocardial ischemia, infarction and fibrosis. More specifically, my work focused on the function of VN in modulation of cardiomyocyte contractility, its effects on cardiac function, and regulation of extracellular matrix degradation in ischemic and infarcted hearts. In vitro and in vivo models have been employed to study the detailed role of VN at sites of ischemia and infarction. Isolated neonatal and adult rat cardiomyocytes, as well as left anterior descending (LAD) coronary artery-ligated transgenic mice have been used to investigate post-MI function and left ventricular (LV) healing. The main findings in this work include the demonstration that during ischemia and infarction VN modulates post-MI myocardial repair/remodeling and cardiac function. VN enters ischemic cardiomyocytes and binds to sarcomeric desmin intermediate filaments apparently causing significant reduction in cardiomyocyte contractility. Further, following infarction VN affects myocardial wound healing by regulating the PA/plasmin and matrix metalloproteinase systems. As well, exercise training in a rat model of LAD ligation induced cardiomyocytes to synthesize and secrete tissue-type plasminogen activator, which may have a role in myocardial healing post-MI. My work on myocardial healing and repair in experimental MI models indicates a potentially important role for plasma proteins such as VN on the PA/plasmin system.

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