MACROPHAGE CHOLESTEROL EFFLUX IN ATHEROSCLEROSIS

动脉粥样硬化中的巨噬细胞胆固醇流出

• 批准号: 2225323
• 负责人: Richard W ST CLAIR
• 金额: $ 22.82万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2225323
• 关键词: aorta; atherosclerosis; atherosclerotic plaque; bone marrow transplantation; cholesterol esters; disease /disorder proneness /risk; enzyme activity; family genetics; genetic models; genetic strain; laboratory mouse; laboratory rabbit; lipase; macrophage; molecular pathology; pigeons; polymerase chain reaction; radiotracer; tissue /cell culture; whole body irradiation effect

Atherosclerosis is a disease of multiple etiology that is influenced by a variety of risk factors. Risk factors, however, can explain only a portion of the variability in this disease. The remaining unexplained variability is due, at least in part, to genetic factors mediated at the level of the arterial wall. The proposed studies will address potential genetically-mediated arterial wall factors by utilizing breeds of pigeons that are genetically susceptible (White Carneau, WC) or resistant (Show Racer, SR) to aortic atherosclerosis. Macrophages play an important role in the pathogenesis of atherosclerosis in pigeons, as they do in man. Although both WC and SR macrophages accumulate large amounts of cholesteryl esters when incubated with certain abnormal lipoproteins, there is no difference in the amount of cholesteryl esters that accumulate in macrophages from the two breeds. SR macrophages in culture, however, are able to efflux this excess cholesterol efficiently to an appropriate acceptor in the medium while, under the same conditions, WC macrophages are defective in cholesterol efflux. The purpose of the proposed studies is to define the cellular and molecular mechanism(s) responsible for this defect in cholesterol efflux and to test the hypothesis that susceptibility to atherosclerosis in the WC pigeon is mediated by an abnormality in cholesterol homeostasis in their macrophages resulting from a defect in cholesterol efflux. Three specific aims are proposed to test this hypothesis. Specific Aim 1 will determine the cellular and molecular mechanisms responsible for the lower rate of cholesterol efflux from cultured WC macrophages. Unlike most published studies, these studies will use macrophages in culture that are loaded with cholesteryl esters to levels found in macrophage foam cells from atherosclerotic plaques. This is accomplished by loading elicited pigeon peritoneal macrophages in vitro with cholesteryl esters or using macrophages from hypercholesterolemic pigeons that are already loaded with cholesteryl esters. Using a variety of agents to stimulate or inhibit potential regulatory steps in cellular cholesterol homeostasis, the proposed studies will determine how cholesterol efflux is regulated in pigeon macrophage foam cells, and the site of the defect in cholesterol efflux in WC macrophages. Specific Aim 2 will determine the extent to which individual variability in aortic atherosclerosis in WC pigeons is correlated with the defect in their macrophages to efflux cholesterol (expt. 1), and if differences in cholesterol efflux potential from macrophages cultured in vitro can be used to predict the subsequent severity of development of atherosclerosis (expt. 2). Specific Aim 3 will test directly the hypothesis that this defect in WC macrophages is responsible for their enhanced atherosclerosis. This will be done by transplanting macrophages from SR pigeons into WC pigeons and vice versa, and studying its effect on the extent and severity of experimental atherosclerosis.

动脉粥样硬化是一种多种病因的疾病， 各种风险因素。 然而，风险因素只能解释 这种疾病的变异性。 剩下的无法解释的 变异性是由于，至少部分是由于遗传因素介导的， 动脉壁的水平。 拟议的研究将探讨潜在的 利用鸽子品种的遗传介导的动脉壁因子 遗传易感（白色白葡萄酒，WC）或耐药（显示 Racer，SR）至主动脉粥样硬化。 宏观调控发挥重要作用 在鸽子动脉粥样硬化的发病机制中的作用，就像在人类中一样。 虽然WC和SR巨噬细胞都积累了大量的 胆固醇酯当与某些异常脂蛋白一起孵育时， 胆固醇酯的量没有差异， 在两个品种的巨噬细胞中积累。 SR巨噬细胞 然而，培养物能够有效地排出这种过量的胆固醇， 在介质中适当的受体，而在相同的 在某些条件下，WC巨噬细胞在胆固醇流出方面有缺陷。 的 拟议研究的目的是确定细胞和分子 导致这种胆固醇流出缺陷的机制， 检验WC中动脉粥样硬化的易感性 鸽子是由胆固醇稳态异常介导的， 胆固醇流出缺陷导致的巨噬细胞。 三 提出了具体目标来检验这一假设。 具体目标1将 确定细胞和分子机制负责较低的 培养的WC巨噬细胞的胆固醇流出率。 不像大多数 发表的研究，这些研究将使用巨噬细胞培养， 在巨噬细胞泡沫细胞中发现的胆固醇酯水平 动脉粥样硬化斑块 这是通过加载引发的 鸽腹腔巨噬细胞在体外与胆固醇酯或使用 高胆固醇血症鸽子的巨噬细胞 胆固醇酯 使用各种药剂刺激或 抑制细胞胆固醇稳态中潜在的调节步骤， 这项研究将确定胆固醇流出是如何被调节的， 在鸽子巨噬细胞泡沫细胞中， WC巨噬细胞中的胆固醇流出。 具体目标2将决定 WC中主动脉粥样硬化的个体差异程度 鸽子与其巨噬细胞的缺陷有关， 胆固醇（expt. 1），如果胆固醇流出潜力的差异 可以用来预测随后的 动脉粥样硬化发展的严重程度（expt. 2）。 具体目标3 将直接检验WC巨噬细胞中的这种缺陷是 导致了动脉粥样硬化 会来做这项工作 将SR鸽的巨噬细胞移植到WC鸽中，反之亦然， 并研究其对实验性 动脉粥样硬化