Cardiac hypertrphy is the most important contributor to cardiovascular morbidity and mortality in western societies. Caridac hypertrophy develops in order to maintain cardiac function against an increasing workload. Early in the process, this hypertrophic response may be beneficial but sustained hypertrophic activation ultimately leads to myocardial dysfunction. Interestingly, the intracellular pathways controlling the development of hypertrophy and which mediate the progression from hypertrophy to heart failure are unclear. Timely activation of humoral factors, such angiotensin II (ANG II) and insulin-like-growth factor-1 (IGF-1), delineate the activation processes of specific protein kinases whose integrated responses leads to the early beneficial cardiac hypertrophy and later to heart failure. IGF-1 administration can induce hypertrophy as well as block cardiac apoptosis;however ANG II can activate both processes. In the heart, activation of phophatidylinositol (PI) 3-kinase is critical to the ability of IGF-1 to block apoptosis. In contrast, the Ras/MAP (mitogen-activated protein) kinase pathway, which can be activated by both IGF-1 and ANG II, has been associated with cardiac hypertrophy. We have found that compensated eccentric cardiac hypertrophy is associated with enhanced activation of these kinases;whereby alterations in potassium and calcium ion channels induced by ANG II and IGF-1 are mainly mediated through MAP kinase and PI 3- kinase activation. The goals of this porposal is to understand the biological roles of specific downstream signaling pathways in controlling cardiocyte apoptosis and hypertrophy, and to delineate the contribution of apoptosis to the development of heart failure. This porposal is based on 3 hypotheses: 1) signaling pathways responsible for the ability of IGF-1 to induce hypertrophy and block apoptosis are distinct;2) activation of PI 3-kinase accounts for the benefial effects of IGF-1 on cardiocyte survival;and 3) apoptosis contributes to the development of cardiac dysfunctin in heart failure. To test these hypotheses, we will use adenoviral vectors to express wild-type and mutant-forms of specific signaling molecules in cardiocytes. The long term goal is understanding the role of specific signaling pathways in cardiocyte apoptosis and developing approaches to local modulation of these pathways through somatic gene transfer;which may provide novel therapeutic appraoches for the management of many clinically important disorders.
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