Saturated Fatty Acid and Cardiovascular Disease

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The central hypothesis to betested in this proposal is that binding of saturated fatty acid to SR-BI activates AMP kinase which results in the production of eNOS-dependent peroxynitrite and subsequently an increase in atherosclerotic lesions. Reducing total dietary fat intake has been used as a method for reducing the risk of coronary heart disease for decades, however, numerous studies have demonstrated that the type of fat may be more important than the total amount of fat in the diet. Unsaturated fats, such as, n-3 and n-6 fatty acids are thought to be anti-atherogenic whereas saturated fatty acids with 14-16 carbon atoms (i.e., myristic acid and palmitic acid) are considered to be pro-atherogenic. Saturated fatty acids are thought to be pro-atherogenic, in part, by causing an increase in total plasma cholesterol levels. Although plasma cholesterol levels clearly influence the development of atherosclerotic lesions cholesterol is only one factor in the multi-factorial disease of atherosclerosis. Our preliminary studies demonstrate that saturated fatty acid can cause an increase in atherosclerosis independent of changes in plasma cholesterol levels. The goal of this proposal is to determine the mechanism whereby saturated fatty acid promotes atherosclerosis without altering plasma cholesterol. The preliminary data suggest that a novel signaling mechanism exists for saturated fatty acids that involve SR-BI, caveolin, AMP kinase, and eNOS which subsequently results in the generation of the pro- atherogenic compound, peroxynitrite. Three specific aims are proposed. Aim 1: To determine the domains within SR-BI that interact with saturated fatty acids and caveolin and to determine the domain within caveolin that interacts with SR-BI. Aim 2: To elucidate the residue(s) in caveolin that are phosphorylated and the domains within caveolin and AMP kinase that interact. Aim 3: To determine if an endothelial-specific caveolin null mouse is protected from saturated fatty acid-induced peroxynitrite production andsubsequently atherosclerosis.