ESTROGENS, MACROPHAGE FOAM CELLS AND ATHEROSCLEROSIS

雌激素、巨噬细胞泡沫细胞和动脉粥样硬化

• 批准号: 6184038
• 负责人: Richard W ST CLAIR
• 金额: $ 28.02万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184038
• 关键词: Animalia; apolipoprotein E; artery; atherosclerosis; blood lipoprotein metabolism; cell line; cholesterol; cholesterol esters; enzyme biosynthesis; enzyme mechanism; estradiol; estrogens; glycoprotein biosynthesis; hormone regulation /control mechanism; human tissue; hydrolysis; lipoprotein lipase; macrophage; monocyte; protein metabolism; protein structure function; proteoglycan; tissue /cell culture

DESCRIPTION (Adapted from Investigator's Abstract): It is well established that women are protected from atherosclerosis and coronary heart disease relative to men, and that this protection is lost after menopause. Estrogen replacement restores much of this lost protection. Nonetheless, the mechanisms by which estrogens exert this protection are poorly understood. Changes in plasma lipoproteins can explain only a small part of this protection and a considerable body of data points to a direct effect of estrogens on the arterial wall. Although the mechanism by which estrogens protect against development of atherosclerosis at the level of the arterial wall is unknown, studies with non human primates and rabbits and preliminary data from macrophages in culture, suggest a direct effect of estrogens on macrophages that reduces cholesterol accumulation and ultimately foam cell formation. The purpose of the proposed studies is to define the cellular mechanism(s) by which estrogens modify the excessive accumulation of cholesterol in macrophages leading to reduced foam cell development. The studies will utilize the human THP-1 macrophage cell line and human monocyte macrophages. Specific aim 1 will determine the effect of 17b-estradiol and other estrogens and steroids on metabolism of lipoproteins (LDL, VLDL, beta-VLDL, oxidized LDL, aggregated LDL), thought to be present in the arterial wall, and on intracellular cholesterol balance, with a focus on enzymes responsible for cholesteryl ester synthesis, hydrolysis and cholesterol efflux. Specific aim 2 will address estrogen modulation of cell surface proteoglycan synthesis, metabolism and structure and subsequent effects on lipoprotein uptake and cholesterol accumulation mediated by cell surface proteoglycans. The role of estrogens on the synthesis and secretion of potential modulators of lipoprotein proteoglycan interactions, such as lipoprotein lipase and apo E, also will be studied. These investigators believe that these studies represent one of the first comprehensive investigations of the role of estrogens on macrophage foam cell development. As a result, important new information on one of the potential mechanisms by which estrogens may reduce atherosclerosis at the level of the arterial wall could be forthcoming.

描述(改编自《调查者摘要》)：很有说服力 保护女性免受动脉粥样硬化和冠心病的危害 相对于男性，这种保护在绝经后就会消失。雌激素 更新换代可以恢复大部分失去的保护。尽管如此， 雌激素发挥这种保护作用的机制还知之甚少。 血浆脂蛋白的变化只能解释其中的一小部分 保护和大量数据表明， 动脉壁上的雌激素。尽管雌激素的作用机制 在动脉水平上预防动脉粥样硬化的发展 墙是未知的，对非人类灵长类动物和兔子的研究和初步 来自巨噬细胞培养的数据表明，雌激素对 巨噬细胞，减少胆固醇积聚，最终减少泡沫细胞 队形。拟议研究的目的是定义细胞 雌激素调节雌激素过度蓄积的机制(S) 巨噬细胞中的胆固醇导致泡沫细胞发育减少。这个 研究将利用人类THP-1巨噬细胞系和人类单核细胞 巨噬细胞。具体目标1将确定17b-雌二醇和 其他雌激素和类固醇对脂蛋白(低密度脂蛋白、极低密度脂蛋白、 β-极低密度脂蛋白，氧化低密度脂蛋白，聚集低密度脂蛋白)，被认为存在于 动脉壁和细胞内胆固醇平衡，重点是 负责胆固醇酯合成、水解酶和 胆固醇外流。具体目标2将解决雌激素对细胞的调控 表面蛋白多糖的合成、代谢和结构及其后续 细胞对脂蛋白摄取和胆固醇蓄积的影响 表面蛋白多糖。雌激素在合成和分泌中的作用 脂蛋白蛋白多糖相互作用的潜在调节剂，如 脂蛋白脂酶和载脂蛋白E，也将被研究。这些调查人员 相信这些研究代表了第一批全面的 雌激素在巨噬细胞泡沫细胞发育中的作用。 因此，关于潜在机制之一的重要新信息通过 哪些雌激素可以减轻动脉壁水平的动脉粥样硬化 可能即将到来。