Modification of HDL and Macrophage Function in Atherosclerosis

动脉粥样硬化中 HDL 和巨噬细胞功能的改变

• 批准号: 10544067
• 负责人: SEAN Stephen DAVIES
• 金额: $ 36.48万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544067
• 关键词: Aorta; Apolipoprotein E; Apoptotic; Arachidonic Acids; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Automobile Driving; Cells; Cholesterol; Cholesterol Esters; Chronic Kidney Failure; Coronary artery; Development; Disease; Enzymes; Equilibrium; Family; GPR55 receptor; Gene Expression; Goals; High Density Lipoproteins; Hydrolysis; Inflammation; Inflammatory; Intestines; Kidney Diseases; Lesion; Ligands; Lipids; Lymph; Lysine; Macrophage; Modeling; Modification; Mus; NAPE-PLD; Necrosis; Patients; Pattern Recognition; Pattern recognition receptor; Peripheral; Phagocytosis; Phenotype; Play; Probability; Proteins; Reducing diet; Rest; Role; Rupture; Small RNA; Testing; Tissues; adduct; cytokine; human disease; hypercholesterolemia; inhibitor; ketoaldehyde; mesenteric lymph node; microbial; mortality; novel; peroxidation; protein expression

A major factor in mortality from atherosclerotic cardiovascular disease is the formation and expansion of necrotic cores within lesions, which arise when macrophages that normally carry out efferocytosis (phagocytosis of apoptotic cells) fail to clear apoptotic cells and instead undergo secondary necrosis. This project seeks to elucidate the contribution of two families of lipids, isolevuglandins (IsoLG) and N- acylethanolamides (NAEs), that potentially interact through HDL to altered macrophage efferocytic function, as well as the role of Nape-pld, an enzyme that catalyzes both the formation of NAEs and the degradation of the IsoLG adducts. We hypothesize that under normal conditions HDL promotes the ability of macrophages to carry out efferocytosis by 1) accepting the cholesterol that macrophages take up during phagocytosis of apoptotic cells and 2) delivering NAE precursors to macrophages which use their Nape-pld to hydrolyze these precursors to NAEs which can promote expression of genes needed for efferocytosis. We hypothesize that in conditions that promote atherosclerosis, HDL becomes modified by IsoLG which retards efferocytosis by 1) inhibiting HDL's ability to accept cholesterol and 2) creating ligands recognized by pattern recognition receptors that drive macrophages to a pro-inflammatory phenotype with high expression of inflammatory cytokines and low expression of proteins needed for efferocytosis. Thus, IsoLG modification of HDL and reduced Nape-pld expression combine to suppress the efferocytic capacity of macrophages, leading to the formation and expansion of necrotic cores which create vulnerable atherosclerotic plaques. We will test this hypothesis as follows: Aim 1 will determine if apoAI lysine residues critical to cholesterol efflux are modified by isolevuglandins during development of atherosclerosis. Aim 2 will elucidate the mechanisms whereby HDL modified by lipid dicarbonyls potentiate inflammation in macrophages and determine if these alterations contribute to reduced efferocytosis. Aim 3 will determine the effects of macrophage Nape-pld deletion on atherosclerosis and macrophage efferocytic capacity.

动脉粥样硬化心血管疾病的死亡率的主要因素是形成和膨胀 病变内的坏死核，这是当通常进行吞噬作用的巨噬细胞时会产生 （凋亡细胞的吞噬作用）无法清除凋亡细胞，而是经历继发性坏死。这 项目旨在阐明两个脂质家族的贡献 酰基乙醇酰胺（NAES），可能通过HDL相互作用以改变巨噬细胞的传染性功能 以及Nape-PLD的作用，一种催化NAE的形成和降解的酶 分离加合物。我们假设在正常条件下HDL促进了巨噬细胞的能力 1）接受胆固醇，巨噬细胞在吞噬作用期间造成的胆固醇 凋亡细胞和2）将NAE前体传递到使用其Nape-Pld将其水解的巨噬细胞传递 NAE的前体，可以促进肿瘤性传播所需的基因表达。我们假设在 促进动脉粥样硬化的疾病，HDL被ISLG所改变，将肿瘤的肿瘤病降低1） 抑制HDL接受胆固醇的能力和2）创建通过模式识别认可的配体 将巨噬细胞驱动到促炎的表型的受体具有炎症的高表达 细胞因子和衰减所需的蛋白质表达低。因此，HDL和 降低的Nape-PLD表达结合起来抑制巨噬细胞的传染性能力，导致 坏死核的形成和扩展，产生脆弱的动脉粥样硬化斑块。 我们将测试该假设如下： AIM 1将确定在Isolevuglandins在 动脉粥样硬化的发展。 AIM 2将阐明HDL通过脂质dicarbonyls增强炎症的机制 巨噬细胞并确定这些改变是否有助于降低肿瘤性。 AIM 3将确定巨噬细胞NAPE-PLD缺失对动脉粥样硬化和巨噬细胞的影响 胚细胞能力。