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: 10327718
• 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/10327718
• 关键词: Aorta; Apolipoprotein E; Apoptotic; Arachidonic Acids; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Automobile Driving; Cells; Cholesterol; 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; Modeling; Modification; Mus; N-acylphosphatidylethanolamine; NAPE-PLD; Necrosis; Patients; 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; macrophage; 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血管的形成和扩张