POLYUNSATURATED FATTY ACIDS AND CELL FUNCTION

多不饱和脂肪酸与细胞功能

• 批准号: 6353065
• 负责人: ARTHUR A. SPECTOR
• 金额: $ 22.79万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6353065
• 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 涉及多不饱和脂肪酸的影响 (PUFA) 及其产品对内皮和动脉平滑肌的作用 肌细胞功能。 目的是确定脂质的作用 源自 PUFA 的生物介质和氧化产物 血管调节和动脉粥样硬化形成。 有五个具体目标。 目标 1 将描述过氧化物酶体 β-氧化的功能 花生四烯酸，不同品种之间是否存在竞争 n-6 和 n-3 PUFA 进入该途径。 两个的作用 通过该途径由花生四烯酸生产的产品，12:2n-6 和 16:3n-6，将被探讨，以及这在多大程度上 该途径在内皮细胞和平滑肌细胞中起作用，并且 产生活性氧（ROS）。 目标 2 将检查 PUFA氧化产物的代谢，例如 环氧二十碳三烯酸 (EET)、二羟基二十碳三烯酸 （DHET）和羟基十八碳二烯酸（HODE） 动脉细胞。 通过微血管和大血管处理 EET 将比较血管内皮细胞。假设这些 化合物产生 ROS，从而引发 LDL 氧化 将进行测试，并通过转染来防止这种情况的能力 将探索具有抗氧化酶基因的内皮细胞。 目标 3 将研究 EET 和其他 含氧花生四烯酸代谢物诱导内皮细胞 白细胞粘附分子的激活和表达， 强调转录和翻译控制。 目标4将 利用膜片钳来检验光滑的曝光的假设 肌肉中 PUFA、EET 或相关 PUFA 含量升高 氧化产物影响 Kplus 通道，导致 血管反应性。 目标 5 将检验脂蛋白的假设 脂肪酶诱导富含甘油三酯的脂蛋白的脂肪分解 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 和含氧 PUFA 的作用机制 产品影响涉及的血管功能 动脉粥样硬化及其并发症。