CATABOLISM OF OXIDIZED PHOSPHOLIPIDS BY VASCULAR CELLS

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状态，并被认为是急性加重的结果。 由于斑块不稳定和相关的流动血液突然暴露到内皮下 病变的主要成分。动脉粥样硬化病变的坏死灶由氧化的脂蛋白组成。 含有炎症激动剂和有毒脂质的死亡细胞中的颗粒和物质。 脂蛋白颗粒的氧化使其磷脂碎裂；其中一些产物是化学作用的 衍生的载脂蛋白形成清道夫受体识别的新表位，其他的具有细胞毒性， 还有一些是PAF类似物，从短链的这个受体启动炎症信号 磷脂。PAF启动凝血和白细胞迁移和激活，并被氧化 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并 被脂蛋白相关酶PAF乙酰水解酶灭活。然而，血液中的水解物 比体内清除慢得多，完全缺乏这种酶的人只有一个 小幅增加动脉粥样硬化并发症的风险。我们认为体内清除的主要结果是 从主动摄取到内皮细胞，然后在隔离的环境中代谢。我们发现 APOE“7”高脂血症小鼠体内有血小板活化受体的循环炎性激动剂 因素。我们建议这些累积是因为它们的清除被竞争所吸收的 缺乏这种炎症活性的更丰富的磷脂氧化产物。 氧化的脂蛋白是有毒的，原因不明。我们发现氧化的磷脂改变了线粒体 功能导致与细胞凋亡相关的事件，并建议氧化磷脂内化 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方面的元素 被忽视的从循环中清除有毒磷脂的途径有四个目标：1)定义 细胞外氧化磷脂2)定义内皮细胞对氧化磷脂的摄取和代谢 细胞3)在分子上定义模型系统中氧化的磷脂转运体4)决定 在酵母中运输短链磷脂的系统具有哺乳动物功能同源物。

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.