CASPASES AND MYOCYTE APOPTOSIS IN THE PATHOGENESIS OF MI

点击翻译按钮获取中文摘要

Numerous studies have demonstrated the occurrence of myocyte apoptosis during myocardial infarction (MI). Despite these observations, the most critical question in the field remains undefined: To what extent does myocyte apoptosis contribute to the changes in myocardial structure and function that characterize MI? The caspases, a novel family of cysteine proteases, constitute the final common pathway for apoptosis in all metazoan cells. Indeed the applicant s preliminary data show that blockade of caspase activation markedly inhibits cardiac myocyte apoptosis in vivo. The significance of this result is that caspase inhibition provides a means to determine the contribution of myocyte apoptosis to the pathogenesis of MI. Accordingly, the following aims are proposed: 1. To determine the effect of inhibiting myocyte apoptosis on infarct size, left ventricular dilatation, and systolic dysfunction following MI. Cardiac myocyte apoptosis will be inhibited using complementary pharmacologic and genetic anti-caspase strategies and the effect of apoptosis inhibition on the expected changes in left ventricular size and function post-MI will be assessed. 2. To determine the sufficiency of caspase activation to induce left ventricular dilatation and systolic dysfunction in vivo. A chimeric caspase whose activation is tightly controlled by an otherwise inert ligand will be expressed in the hearts of transgenic mice and changes in left ventricular dimensions and function will be analyzed following caspase activation. Taken together, this research program will define the role of cardiac myocyte apoptosis in the pathogenesis of MI. In so doing, these studies may provide the conceptual framework for novel therapies for ischemic heart disease based on apoptosis inhibition.