Saturated Fatty Acid and Cardiovascular Disease

在这一提议中要检验的中心假设是饱和脂肪酸与SR-BI的结合 激活AMP激酶，导致eNOS依赖性过氧亚硝酸盐的产生， 随后动脉粥样硬化病变增加。 减少总的膳食脂肪摄入量已被用作降低冠心病风险的方法 然而，几十年来，许多研究表明，脂肪的类型可能更多， 比饮食中的脂肪总量更重要。不饱和脂肪，如n-3和n-6脂肪酸， 被认为是抗动脉粥样硬化的而具有14-16个碳原子的饱和脂肪酸（即，肉豆蔻酸和 棕榈酸）被认为是促动脉粥样硬化的。饱和脂肪酸被认为是促动脉粥样硬化的， 部分是通过增加血浆总胆固醇水平。虽然血浆胆固醇水平明显 胆固醇只是影响动脉粥样硬化病变发展的多因素之一 动脉粥样硬化疾病。我们的初步研究表明，饱和脂肪酸可以导致 动脉粥样硬化的增加与血浆胆固醇水平的变化无关。这项提案的目的是 确定饱和脂肪酸促进动脉粥样硬化而不改变血浆 胆固醇初步数据表明，饱和脂肪酸存在一种新的信号机制， 涉及SR-BI、小窝蛋白、AMP激酶和eNOS，其随后导致原- 致动脉粥样硬化化合物过氧亚硝酸盐提出了三个具体目标。 目的1：确定SR-BI中与饱和脂肪酸和小窝蛋白相互作用的结构域 并确定小窝蛋白中与SR-BI相互作用的结构域。 目的2：阐明小窝蛋白磷酸化的残基及其结构域 小窝蛋白和AMP激酶相互作用。 目的3：确定内皮特异性小窝蛋白敲除小鼠是否受到饱和脂肪酸的保护， 酸诱导的过氧亚硝酸盐的产生和随后的动脉粥样硬化。

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.