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.

动脉粥样硬化性心血管疾病死亡的一个主要因素是动脉粥样硬化的形成和扩张 病变内的坏死核心，通常在巨噬细胞进行胞吞作用时出现 （凋亡细胞的吞噬作用）无法清除凋亡细胞，而是发生继发性坏死。这 该项目旨在阐明两个脂质家族的贡献，即异油黄素 (IsoLG) 和 N- 酰基乙醇酰胺 (NAE)，可能通过 HDL 相互作用来改变巨噬细胞的细胞功能，如 以及 Nape-pld 的作用，Nape-pld 是一种催化 NAE 形成和 NAE 降解的酶 IsoLG 加合物。我们假设在正常条件下 HDL 可以促进巨噬细胞的能力 1) 接受巨噬细胞在吞噬过程中摄取的胆固醇，从而进行胞吞作用 凋亡细胞和 2) 将 NAE 前体传递给巨噬细胞，巨噬细胞使用其 Nape-pld 水解这些前体 NAE 的前体，可以促进胞吞作用所需基因的表达。我们假设在 在促进动脉粥样硬化的条件下，HDL 会被 IsoLG 修饰，从而延迟胞吞作用 1) 抑制 HDL 接受胆固醇的能力，2) 产生可被模式识别识别的配体 驱动巨噬细胞达到促炎表型并高表达炎症的受体 胞吞作用所需的细胞因子和蛋白质的低表达。因此，HDL 的 IsoLG 修饰和 减少的 Nape-pld 表达联合抑制巨噬细胞的吞噬能力，​​导致 坏死核心的形成和扩张，形成脆弱的动脉粥样硬化斑块。 我们将按如下方式检验该假设： 目标 1 将确定对胆固醇流出至关重要的 apoAI 赖氨酸残基是否在 动脉粥样硬化的发展。 目标 2 将阐明脂质二羰基修饰的 HDL 增强炎症的机制 巨噬细胞并确定这些改变是否导致胞吞作用减少。 目标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 细胞容量。