Saturated Fatty Acid and Cardiovascular Disease

描述（由申请人提供）：本提案中需要验证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，随后增加动脉粥样硬化病变。几十年来，减少总膳食脂肪摄入量一直被用作降低冠心病风险的方法；然而，许多研究表明，脂肪的种类可能比饮食中脂肪的总量更重要。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，而含有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进动脉粥样硬化，部分原因是引起血浆总胆固醇水平升高。虽然血浆胆固醇水平明显影响动脉粥样硬化病变的发展，但胆固醇只是动脉粥样硬化多因素疾病的一个因素。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，而不依赖于血浆胆固醇水平的变化。该建议的目的是确定饱和脂肪酸在不改变血浆胆固醇的情况下促进动脉粥样硬化的机制。初步数据表明，饱和脂肪酸存在一种新的信号传导机制，涉及SR-BI、小窝蛋白、AMP激酶和eNOS，随后导致促动脉粥样硬化化合物过氧亚硝酸盐的产生。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，以及确定与SR-BI相互作用的小窝蛋白中的结构域。目的2：阐明小窝蛋白磷酸化残基以及小窝蛋白与AMP激酶相互作用的结构域。目的3：确定内皮特异性小窝蛋白缺失小鼠是否可以免受饱和脂肪酸诱导的过氧亚硝酸盐产生和随后的动脉粥样硬化的影响。

DESCRIPTION (provided by applicant): The central hypothesis to be tested 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 and subsequently atherosclerosis.