CATABOLISM OF OXIDIZED PHOSPHOLIPIDS BY VASCULAR CELLS

血管细胞氧化磷脂的分解代谢

• 批准号: 8266510
• 负责人: Thomas M McIntyre
• 金额: $ 38.35万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266510
• 关键词: Abbreviations; Accounting; Acute; Adenine Nucleotides; Affinity; Agonist; Animals; Apolipoprotein E; Apolipoproteins; Apoptosis; Apoptotic; Arterial Fatty Streak; Atherosclerosis; Biological Models; Blood; Blood Circulation; Blood Vessels; Blood flow; Catabolism; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Coagulation Process; Country; Cultured Cells; Disease; Elements; Endothelial Cells; Endothelium; Environment; Enzymes; Epitopes; Event; Genes; Homologous Gene; Human Genome; Hydrolysis; Hyperlipidemia; Immune; Immune system; Individual; Inflammatory; Lecithin; Lesion; Leukocytes; Ligands; Lipids; Lipoprotein (a); Lipoproteins; Low-Density Lipoproteins; Lysophosphatidylcholines; Mammalian Cell; Mediator of activation protein; Metabolic Clearance Rate; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mus; Necrosis; Pathway interactions; Patients; Phenotype; Phospholipids; Phosphorylcholine; Physiological; Plasma; Platelet Activating Factor; Proteins; Rattus; Receptor Signaling; Research Personnel; Risk; Saccharomyces cerevisiae; Signal Transduction; Small Interfering RNA; Structure; Structure of parenchyma of lung; System; Testing; Thrombosis; Tissues; Yeasts; analog; apoptosis inducing factor; cell motility; cytotoxic; extracellular; human AMID protein; hypercholesterolemia; in vivo; lipid mediator; mortality; mutant; oxidation; oxidized lipid; oxidized low density lipoprotein; particle; platelet activating factor receptor; receptor; scavenger receptor; uptake

Atherosclerosis and its complications are leading causes of morbidity and mortality in this country. This disease is now understood to be a chronic inflammatory condition with acute exacerbations thought to result from plaque instability and the associated sudden exposure of flowing blood to the subendothelial lomponents of the lesions. This necrotic core of atherosclerotic lesions is composed of oxidized lipoprotein particles and material from dead cells that contain inflammatory agonists and toxic lipids. Oxidation of lipoprotein particles fragments their phospholipids; some of these products chemically derivitized apolipoproteins to form the neo-epitopes recognized by scavenger receptors, others are cytotoxic, and still others are PAF analogs that initiate inflammatory signaling from this receptor for short chain phospholipids. PAF initiates clotting and white blood cell migration and activation, and oxidized phospholipids that activate this receptor of innate immune cells are pro-thrombotic. These toxic and pro-inflammatory lipid agonists generated by phospholipid oxidation are hydrolyzed and inactivated by a lipoprotein-associated enzyme, PAF acetylhydrolase. However, hydrolysis in blood is significantly slower than clearance in vivo, and individuals who completely lack this enzyme have only a small increased risk of the complications of atherosclerosis. We propose that clearance in vivo mainly results from active uptake into endothelium with subsequent metabolism in a sequestered environment. We find apoE"7" hyperlipidemic mice have circulating inflammatory agonists of the receptor for Platelet-Activating Factor. We propose these accumulate because their clearance is slowed by competition for uptake by the more abundant phospholipid oxidation products that lack such inflammatory activity. Oxidized lipoproteins are toxic for unknown reasons. We find oxidized phospholipids alter mitochondrial function leading to the events associated with apoptosis, and propose oxidized phospholipids internalized by physiologic transport systems initiate cell death in this manner. We will define elements of this previously overlooked pathway to clear toxic phospholipids from the circulation in four aims: 1) Define the fate of extracellular oxidized phospholipids 2) Define oxidized phospholipid uptake and metabolism by endothelial cells 3) Molecularly define oxidized phospholipid transporters in a model system 4) Determine whether the system that transports short chain phospholipids in yeast has functional mammalian homologs.

动脉粥样硬化及其并发症是该国发病率和死亡率的主要原因。这 疾病现在被认为是一种慢性炎症性疾病， 从斑块不稳定性和相关的流动血液突然暴露到内皮下 病变的成分。动脉粥样硬化病变的坏死核心由氧化脂蛋白组成 来自死亡细胞的颗粒和物质，含有炎症激动剂和有毒脂质。 脂蛋白颗粒的氧化使其磷脂碎片化;这些产物中的一些化学 衍生的载脂蛋白形成被清道夫受体识别的新表位，其他的是细胞毒性的， 还有一些是PAF类似物，其启动来自这种短链受体的炎症信号， 磷脂PAF启动凝血和白色血细胞迁移和活化，并氧化 激活这种先天免疫细胞受体的磷脂是促血栓形成的。 这些由磷脂氧化产生的毒性和促炎性脂质激动剂被水解， 被脂蛋白相关酶PAF乙酰水解酶灭活。然而，血液中的水解是 明显慢于体内清除，完全缺乏这种酶的个体只有一个 动脉粥样硬化并发症的风险增加不大。我们认为体内清除主要是由于 从主动摄取进入内皮细胞，随后在隔离环境中代谢。我们发现 apoE“7”高脂血症小鼠具有血小板活化受体的循环炎性激动剂 因子我们认为这些物质的积累是因为它们的清除被竞争吸收而减慢， 更丰富的磷脂氧化产物缺乏这种炎症活性。 氧化脂蛋白是有毒的，原因不明。我们发现氧化磷脂改变了线粒体 功能导致与细胞凋亡相关的事件，并提出氧化磷脂内化， 生理运输系统以这种方式启动细胞死亡。我们将在前面定义这些元素 被忽视的途径，以清除有毒磷脂从循环中的四个目标：1）定义的命运， 2）定义内皮细胞对氧化磷脂的摄取和代谢 细胞3）在模型系统中分子定义氧化磷脂转运蛋白4）确定 在酵母中运输短链磷脂的系统具有功能性哺乳动物同源物。