ApoE and SR-BI as Determinants of HDL and Macrophage Function in Atherogenesis

ApoE 和 SR-BI 作为动脉粥样硬化形成中 HDL 和巨噬细胞功能的决定因素

• 批准号: 7487473
• 负责人: MACRAE F LINTON
• 金额: $ 38.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487473
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Apolipoprotein E; Apoptosis; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Awareness; Bone Marrow Transplantation; Cells; Cessation of life; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Coronary Arteriosclerosis; Coronary heart disease; Dyslipidemias; Employee Strikes; Environment; Foam Cells; Genes; Goals; Grant; HDL cholesteryl ester; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; In Vitro; Inflammation; Inflammatory; Laboratories; Lead; Lipids; Localized; Mediating; Mediation; Metabolism; Modeling; Mus; Myocardial Infarction; Pathway interactions; Phagocytosis; Phenotype; Plasma; Play; Research Personnel; Risk; Role; SR-B proteins; Signal Transduction; Testing; accelerated particle; atherogenesis; atheroprotective; attenuation; cell transformation; hypercholesterolemia; in vivo; insight; lipid metabolism; macrophage; novel therapeutics; oxidation; particle; prevent; programs; reconstitution; reverse cholesterol transport; trafficking; uptake

DESCRIPTION (provided by applicant): Anti-atherogenic functions of HDL cholesterol include mediation of reverse cholesterol transport as well as anti-oxidant and anti-inflammatory effects. Scavenger receptor class B type-l (SR-BI) and apolipoprotein E (apoE) both play crucial roles in HDL metabolism and reverse cholesterol transport. Combined deficiency of SR-BI and apoE (DKO) in mice results in dyslipidemia, characterized by large free cholesterol (FC)-enriched HDL particles, accelerated occlusive coronary disease, and premature death due to myocardial infarction. Our preliminary studies show that DKO HDL particles may be dysfunctional and proatherogenic by inducing FC overload in wild type macrophages. In Specific Aim (SA) 1, we will examine the hypothesis that the DKO HDL cholesterol particles are severely dysfunctional and proatherogenic, promoting oxidation, inflammation, and abnormal reverse cholesterol transport. ApoE may mediate RCT through both SR-BI dependent and independent pathways, and the loss of both pathways may contribute to the lethal phenotype in DKO mice. Macrophage-specific deletion of either apoE or SR-BI promotes atherosclerosis. Our preliminary studies indicate that macrophage deficiency of both apoE and SR-BI results in dramatically impaired cholesterol homeostasis and a striking increase in accumulation of apoptotic cells in atherosclerotic lesions, independent of the DKO lipid environment. These results suggest that DKO macrophages may be prone to FC-induced apoptosis and/or impaired phagocytic clearance of apoptotic cells in atherosclerosis. The goal of SA2 is to test the hypothesis that macrophage apoE and SR-BI cooperate to limit atherogenesis and apoptosis. The abnormal cholesterol homeostasis of DKO macrophages suggests that SR-BI and apoE function in a cooperative fashion to optimize macrophage trafficking and mobilization of cholesterol. In SA3, in vitro studies will examine the hypothesis that SR-BI-associated cholesterol domains and signaling modulate apoE secretion. Studies will also test the hypothesis that apoE containing HDL are the most efficient acceptors of SR-BI mobilized cholesterol. Finally, we will examine the hypothesis that SR-BI and apoE expression impact ABCA1- and ABCG1-mediated trafficking and mobilization of cholesterol. New insights into the roles of apoE and SR-BI as determinants of the anti-atherogenic functions of HDL cholesterol and macrophage cholesterol homeostasis and apoptosis may lead to new therapeutic approaches for atherosclerosis.

描述（由申请人提供）：高密度脂蛋白胆固醇的抗动脉粥样硬化功能包括介导胆固醇逆向转运以及抗氧化和抗炎作用。清道夫受体B类1型（SR-BI）和载脂蛋白E （apoE）在HDL代谢和逆向胆固醇转运中都起着至关重要的作用。SR-BI和apoE （DKO）在小鼠体内的联合缺乏会导致血脂异常，其特征是大量的游离胆固醇（FC）富集的HDL颗粒，加速闭塞性冠状动脉疾病，以及心肌梗死导致的过早死亡。我们的初步研究表明，DKO HDL颗粒可能通过诱导野生型巨噬细胞FC过载而功能失调和致动脉粥样硬化。在Specific Aim (SA) 1中，我们将检验DKO HDL胆固醇颗粒严重功能失调和致动脉粥样硬化的假设，促进氧化、炎症和异常的逆向胆固醇运输。ApoE可能通过SR-BI依赖性和非依赖性途径介导RCT，这两种途径的缺失可能导致DKO小鼠的致死性表型。巨噬细胞特异性缺失apoE或SR-BI均可促进动脉粥样硬化。我们的初步研究表明，巨噬细胞缺乏apoE和SR-BI会导致胆固醇稳态显著受损，并显著增加动脉粥样硬化病变中凋亡细胞的积累，而不依赖于DKO脂质环境。这些结果表明，动脉粥样硬化中DKO巨噬细胞可能容易发生fc诱导的凋亡和/或凋亡细胞的吞噬清除受损。SA2的目的是验证巨噬细胞apoE和SR-BI共同限制动脉粥样硬化和细胞凋亡的假设。DKO巨噬细胞异常的胆固醇稳态表明，SR-BI和apoE协同作用，优化巨噬细胞运输和胆固醇动员。在SA3中，体外研究将检验sr - bi相关胆固醇结构域和信号传导调节apoE分泌的假设。研究还将验证含有载脂蛋白e的高密度脂蛋白是SR-BI动员胆固醇的最有效受体的假设。最后，我们将检验SR-BI和apoE表达影响ABCA1-和abcg1介导的胆固醇运输和动员的假设。apoE和SR-BI作为高密度脂蛋白胆固醇和巨噬细胞胆固醇稳态和凋亡的抗动脉粥样硬化功能决定因素的新见解可能会导致动脉粥样硬化的新治疗方法。