Saturated Fatty Acid and Cardiovascular Disease

饱和脂肪酸与心血管疾病

• 批准号: 7367195
• 负责人: Eric J Smart
• 金额: $ 35.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367195
• 关键词: 5' -AMP-activated protein kinase; Acids; Antiatherogenic; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Bos taurus; Breeding; Carbon; Cardiovascular Diseases; Cattle; Caveolins; Cell membrane; Cells; Cholesterol; Coronary; Coronary heart disease; Data; Development; Diet; Dietary Fats; Disease; Endothelial Cells; Fatty Acids; Fatty acid glycerol esters; Fibrinogen; Generations; Goals; Intake; Knockout Mice; Ligands; Low Density Lipoprotein Receptor; Methods; Modeling; Mus; Mutate; Myristic Acids; Nitric Oxide; Palmitic Acids; Peroxonitrite; Phosphorylation; Plasma; Production; Reactive Oxygen Species; Recruitment Activity; Research Personnel; Risk; Saturated Fatty Acids; Signal Transduction; Standards of Weights and Measures; System; Thinking; Unsaturated Fats; adenylate kinase; base; caveolin 1; feeding; novel; programs; receptor

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.

该提案要测试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。 减少膳食脂肪摄入总量已被用作降低冠心病风险的方法 然而，数十年的疾病史，大量研究表明，脂肪的类型可能更重要。 比饮食中的脂肪总量更重要。不饱和脂肪，例如 n-3 和 n-6 脂肪酸 被认为具有抗动脉粥样硬化作用，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， 部分原因是导致血浆总胆固醇水平升高。尽管血浆胆固醇水平明显 影响动脉粥样硬化病变的发展胆固醇只是多因素中的一个因素 动脉粥样硬化疾病。我们的初步研究表明，饱和脂肪酸会导致 动脉粥样硬化的增加与血浆胆固醇水平的变化无关。该提案的目标是 确定饱和脂肪酸在不改变血浆的情况下促进动脉粥样硬化的机制 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、caveolin、AMP 激酶和 eNOS，随后导致 pro- 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。 目标 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 Caveolin 内与 SR-BI 相互作用的结构域。 目标 2：阐明 Caveolin 中被磷酸化的残基及其结构域 Caveolin 和 AMP 激酶相互作用。 目标 3：确定内皮特异性小窝蛋白缺失小鼠是否免受饱和脂肪的影响 酸诱导的过氧亚硝酸盐的产生以及随后的动脉粥样硬化。