POLYUNSATURATED FATTY ACIDS AND CELL FUNCTION

多不饱和脂肪酸与细胞功能

• 批准号: 6495732
• 负责人: ARTHUR A. SPECTOR
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6495732
• 关键词: antioxidants; arachidonate; atherosclerosis; blood lipoprotein metabolism; eicosanoid metabolism; eicosanoids; fatty acid metabolism; free radical oxygen; free radicals; gene expression; leukocyte adhesion molecules; lipid transport; lipoprotein lipase; low density lipoprotein; oxidation; potassium channel; tissue /cell culture; unsaturated fatty acids; vascular endothelium; vascular smooth muscle; voltage /patch clamp

Project 1 deals with the effects of polyunsaturated fatty acids (PUFA) and their products on endothelial and arterial smooth muscle cell function. The objective is to determine the role of lipid biomediators and oxidation products derived from PUFA in vascular regulation and atherogenesis. There are five specific aims. Aim 1 will delineate the function of peroxisomal beta-oxidation of arachidonic acid, and whether there is competition between different n-6 and n-3 PUFA for entry into this pathway. The function of two products produced from arachidonic acid by this pathway, 12:2n-6 and 16:3n-6, will be explored, as well as the extent to which this pathway operates in endothelial and smooth muscle cells and generates reactive oxygen species (ROS). Aim 2 will examine the metabolism of PUFA oxidation products such as epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and hydroxyoctadecadienoic acids (HODEs) by the arterial cells. The handling of EETs by microvessel and large vessel endothelial cells will be compared. The hypothesis that these compounds generate ROS and can thereby trigger LDL oxidation will be tested, and the ability to protect against this by transfecting endothelial cells with antioxidant enzyme genes will be explored. Aim 3 will investigate the mechanism by which EETs and other oxygenated arachidonic acid metabolites induce endothelial activation and the expression of leukocyte adhesion molecules, with emphasis on transcriptional and translational control. Aim 4 will utilize patch clamping to test the hypothesis that exposure of smooth muscle to elevated amounts of PUFA, EETs, or related PUFA oxidation products affects Kplus channels, leading to changes in vascular reactivity. Aim 5 will test the hypothesis that lipoprotein lipase induced lipolysis of triglyceride-rich lipoproteins and lipoproteins that contain oxidized lipids can adversely affect the function of endothelial cells. These data will provide basic new insight into the mechanisms by which PUFA and oxygenated PUFA products affect vascular functions that are involved in atherosclerosis and its complications.

项目1处理多不饱和脂肪酸的影响 （PUFA）及其在内皮和动脉平滑的产品 肌肉细胞功能。 目的是确定脂质的作用 来自PUFA的生物介质和氧化产物 血管调节和动脉粥样硬化。 有五个具体目标。 AIM 1将描述过氧化物酶体β-氧化的功能 花生四烯酸，以及不同之间是否存在竞争 N-6和N-3 PUFA进入此途径。 两个功能 通过这种途径从蛛网膜化产生的产品，12：2n-6 将探索16：3n-6，以及在此的程度 途径在内皮和平滑肌细胞中运行， 产生活性氧（ROS）。 AIM 2将检查 PUFA氧化产物的代谢，例如 环氧气酸（EET），二羟基乙酸酸酯酸酸（Eet） （DHET）和羟基二糖酸（HODES） 动脉细胞。 通过微血管和大型处理Eets 将比较血管内皮细胞。这些假设是 化合物产生ROS，从而触发LDL氧化 将测试，并通过转染来防止这种情况 将探索具有抗氧化酶基因的内皮细胞。 AIM 3将研究Eets和其他Eets的机制 氧化的花生四烯酸代谢产物诱导内皮 白细胞粘附分子的激活和表达，具有 强调转录和翻译控制。 目标4意志 利用斑块夹子来测试平滑暴露的假设 肌肉升高的PUFA，EET或相关PUFA 氧化产物影响KPLUS通道，导致 血管反应性。 AIM 5将检验脂蛋白的假设 脂肪酶诱导富含甘油三酸酯的脂蛋白的脂解和 含有氧化脂质的脂蛋白会对 内皮细胞的功能。 这些数据将提供基本的新 深入了解PUFA和氧化PUFA的机制 产品影响涉及的血管功能 动脉粥样硬化及其并发症。