Saturated Fatty Acid and Cardiovascular Disease

饱和脂肪酸与心血管疾病

• 批准号: 7787052
• 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/7787052
• 关键词: 5' -AMP-activated protein kinase; Acids; Antiatherogenic; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; 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; System; 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.

在这一提议中更好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依赖的过氧亚硝酸盐的产生，并 随之而来的动脉粥样硬化病变增多。 减少膳食总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，无数的研究表明，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进动脉粥样硬化的物质， 部分原因是导致血浆总胆固醇水平上升。尽管血浆胆固醇水平很明显 影响动脉粥样硬化病变发展的多因素中胆固醇只是一个因素 动脉粥样硬化症。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。这项提议的目标是 在不改变血浆的情况下确定饱和脂肪酸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。 它涉及SR-BI、小窝蛋白、AMP激酶和eNOS，从而导致PRO-BI的产生。 致动脉粥样硬化的化合物，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 并确定小窝蛋白中与SR-BI相互作用的结构域。 目的2：阐明洞穴蛋白中被磷酸化的残基(S)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缺失小鼠是否受到饱和脂肪的保护 酸诱导的过氧亚硝酸盐的产生和随后的动脉粥样硬化。