Impairment of endothelial function, which is a hallmark of atherosclerosis in experimental animal and humans, may contribute to development of atherosclerosis and its complications. The overall theme of this Program is mechanisms of dysfunction of endothelium and vascular muscle in atherogenesis. The investigators propose to integrated physiological and molecular approaches to examine mechanisms by which risk factors and oxidants may produce atherosclerosis. The Program consists of three projects and an administrative core. Project 1 tests the hypothesis that angiotensin II contributes to increased levels of superoxide in blood vessels and that this mechanism may contribute to acceleration of atherosclerosis by hypertension. Two novel hypertensive transgenic mice have been made to test this hypothesis. Circulating levels of angiotensin II are markedly elevated in one model, and normal in the other model; the degree of hypertension, however, is similar in the two models. These models will allow a new approach to examine the role of angiotensin in vascular changes during hypertension and atherosclerosis. The investigators in Project 2 have reported recently that, in contrast to previous studies which have focused on the role of reactive oxygen species (ROS) generated by endothelium, vascular muscle is a major source of superoxide in atherosclerotic vessels. Studies are proposed to determine the important of, and examine enzymatic mechanisms that account for, production of superoxide by smooth muscle in atherosclerotic vessels. Studies are proposed to determine the importance of, and examine enzymatic mechanisms that account for, production of superoxide smooth muscle in atherosclerotic vessels. Studies are planned in a genetic model of atherosclerosis in mice, and in a primate model of atherosclerosis and repression. Project 3 proposes to test the hypothesis that excessive production of ROS may regulate both proliferation and promote death of smooth muscle cells. Gene transfer approaches will be used to directly increase concentration of antioxidant enzymes, rather than using topical application of the enzymes, Studies are planned to determine whether endogenous H2O2, and the balance between superoxide and H2O2, regulate both proliferation and viability of smooth muscle cells. The studies will examine mechanisms that account for enhanced susceptibility of neointimal smooth muscle cells to cytotoxicity by RO2. Target goals of the Program include clarification include clarification of mechanisms by which risk factors produce atherosclerosis, insight into cellular and enzymatic sources of reactive oxygen species in atherosclerotic vessels, and better understanding of potential therapeutic targets, including oxidative processes, angiotensin II, and hyperlipidemia.
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