ESTROGENS, MACROPHAGE FOAM CELLS AND ATHEROSCLEROSIS

描述（改编自研究者摘要）：已确立 保护女性免受动脉粥样硬化和冠心病的侵害 相对于男性，这种保护在绝经后失去。 雌激素 更换可以恢复大部分失去的保护。 不过 雌激素发挥这种保护作用的机制知之甚少。 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 虽然雌激素 防止动脉粥样硬化的发展 壁是未知的，研究与非人灵长类动物和兔和初步 来自培养物中巨噬细胞的数据表明雌激素对 巨噬细胞，减少胆固醇积累，最终泡沫细胞 阵 拟议研究的目的是确定细胞 雌激素调节过度积累的机制 巨噬细胞中的胆固醇导致泡沫细胞发育减少。 的 研究将利用人THP-1巨噬细胞系和人单核细胞 巨噬细胞 具体目标1将确定17 b-雌二醇的作用， 其它雌激素和类固醇对脂蛋白（LDL，VLDL， β-VLDL，氧化LDL，聚集LDL），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、水解和 胆固醇流出 具体目标2将解决雌激素调节细胞 表面蛋白聚糖合成、代谢和结构以及随后的 对细胞介导的脂蛋白摄取和胆固醇蓄积的影响 表面蛋白聚糖 雌激素在合成和分泌中的作用 脂蛋白蛋白聚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。 这些研究者 我相信这些研究是第一个全面的 雌激素对巨噬细胞泡沫细胞发育作用的研究。 因此，关于潜在机制之一的重要新信息， 哪些雌激素可以减少动脉壁水平的动脉粥样硬化 可能即将到来。

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.