CATABOLISM OF OXIDIZED PHOSPHOLIPIDS BY VASCULAR CELLS

血管细胞氧化磷脂的分解代谢

• 批准号: 7700666
• 负责人: Thomas M McIntyre
• 金额: $ 38.37万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7700666
• 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这个国家发病率和死亡率的主要原因。这