CATABOLISM OF OXIDIZED PHOSPHOLIPIDS BY VASCULAR CELLS

血管细胞氧化磷脂的分解代谢

• 批准号: 7337246
• 负责人: Thomas M McIntyre
• 金额: $ 39.04万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337246
• 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 physiology; Cells; Chronic; Coagulation Process; Condition; 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); Lipoprotein (a-); Lipoproteins; Localized; 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; Rate; Rattus; Receptor Signaling; Research Personnel; Risk; Saccharomyces cerevisiae; Signal Transduction; Small Interfering RNA; Structure; Structure of parenchyma of lung; System; Testing; Thinking; 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 现在认为疾病是一种慢性炎症状况，急性加重被认为会导致 从斑块不稳定性和流动血液突然暴露于下皮 病变的lomponents。动脉粥样硬化病变的这种坏死核心由氧化脂蛋白组成 含有炎症激动剂和有毒脂质的死细胞的颗粒和材料。 脂蛋白颗粒的氧化其磷脂碎片；这些产品中的一些化学 衍生化的载脂蛋白形成了被清道夫受体识别的新观点，其他是细胞毒性的， 还有一些是PAF类似物，从该受体发起炎症信号转导，用于短链 磷脂。 PAF引发凝结，白细胞迁移和激活，并氧化 激活这种先天免疫细胞受体的磷脂是促血统的。 这些由磷脂氧化产生的有毒和促炎性脂质激动剂被水解，并且 被脂蛋白相关酶，PAF乙酰水合酶灭活。但是，血液中的水解是 体内比清除率明显慢，完全缺乏这种酶的个体只有一个 小幅增加动脉粥样硬化并发症的风险。我们建议在体内清除率主要是结果 从积极摄取对内皮的摄取，随后在隔离环境中代谢。我们发现 APOE“ 7”高脂小鼠具有循环的受体炎性激动剂，用于血小板激活 因素。我们建议这些积累，因为它们的清除因吸收竞争而放缓 缺乏这种炎症活性的更丰富的磷脂氧化产物。 氧化的脂蛋白由于未知原因有毒。我们发现氧化的磷脂改变了线粒体 功能导致与凋亡相关的事件，并提出由 生理运输系统以这种方式引发细胞死亡。我们将定义以前的元素 从四个目标中清除循环中清除有毒磷脂的途径：1）定义 细胞外氧化磷脂2）定义内皮的氧化磷脂摄取和代谢 细胞3）分子在模型系统中定义氧化的磷脂转运蛋白4） 运输酵母中短链磷脂的系统具有功能性哺乳动物同源物。