The objective of this proposal is to investigate the mechanisms responsible for the protective role of the kallikrein-kinin system (KKS) on ventricular dysfunction and cardiac remodeling in ischemic and hypertrophic cardiomyopathies. During the current funding period, we have made new and exciting findings indicating that enhanced kallikrein/kinin levels provide multiple functions, such as blood pressure reduction, improvement of cardiac and renal function, and protection against cardiovascular and renal injury in hypertensive and normotensive animal models. Our preliminary studies showed that the protective effects of kallikrein gene transfer in the heart, kidney and brain are accompanied by 1) increased kinin and NO levels, 2) reduced NAD(P)H oxidase activity, superoxide formation and TGF-beta levels, and 3) activation of Akt signaling. Based on these results, we hypothesize that kallikrein-kinin protects against organ damage and improves cardiomyocyte survial through increased NO formation, suppressed oxidative stressinduced signaling, and activation of Akt-mediated signaling pathways. We intend to fulfill the following specific aims: 1) determine the signaling mechanisms responsible for the anti-apoptotic effect of kallikrein/kinin in a rat model of acute myocardial ischemia/reperfusion injury and in cultured cardiomyocytes, 2) determine the signaling mechanisms responsible for the anti-hypertrophic effect of kallikrein/kinin in a rat model of aortic banding and in cultured cardiomyocytes, and 3) determine the signaling mechanisms responsible for the anti-fibrotic effect of kallikrein/kinin on cardiac remodeling in a rat model of myocardial infarction and in cultured cardiac fibroblasts. Enhanced kallikrein/kinin levels in the heart will be achieved by local delivery of the human tissue kallikrein gene into animal models, or using transgenic rats over-expressing human tissue kallikrein. Cellular mechanisms will be dissected by using dominant-negative DNA constructs, small interfering RNAs, specific inhibitors or antibody at the specific steps. The protective role of kinin will be further analyzed using kinin B1 and B2 receptor knockout mice. Our long-term goal is to understand the role and mechanisms mediated by KKS in protection against cardiac remodeling and the progression to heart failure. This study should generate new and important information to provide the impetus for developing therapeutic regimens to prevent heart failure in man.
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