HDL, Inflammation and Atherosclerosis

HDL、炎症和动脉粥样硬化

• 批准号: 7140039
• 负责人: ALAN CHAIT
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140039
• 关键词: atherosclerosis; atherosclerotic plaque; cell cell interaction; cell type; clinical research; disease /disorder model; extracellular; gene expression; high density lipoproteins; human subject; hypercholesterolemia; inflammation; intracellular; laboratory mouse; lead; lipids; macrophage; protein structure function; smooth muscle; vascular endothelium

High density lipoprotein (HDL) plays a critical role in preventing CVD. Inflammation is of central importance in the pathogenesis of atherosclerosis. Chronic inflammation leads to changes in HDL [e.g. decreased apolipoprotein A-l (apo A-l) and paraoxonase (PON1), and increased SAA and other novel proteins identified by mass spectrometry]. These changes are associated with a loss of its atheroprotective properties. Inflammation also may lead to pro-atherogenic changes in HDL. We hypothesize that compositional and functional changes in HDL induced by inflammation provides an important link between inflammation and atherosclerosis. We also hypothesize that changes in HDL composition may be biomarkers that indicate the presence of oxidative damage and/or atherosclerosis at the level of the artery wall. To test these hypotheses, we plan to determine how inflammation (acute and chronic) influences HDL composition, function and role in atherogenesis in mice. Next, we will test the mechanism by which inflammation reduces the atheroprotective HDL apolipoproteins apo A-l and PON1, and increases the potentially proatherogenic apolipoprotein SAA in HDL. Third, we will determine whether local over-expression by macrophages of inflammatory and anti-inflammatory proteins present in HDL affects the initiation and/or progression of atherosclerosis in a mouse model of hypercholesterolemia. Finally, we will determine whether chronic inflammation alters the composition and functional properties of HDL in humans in a manner similar to that in mice, and whether changes in HDL protein composition are markers of oxidation and/or atherosclerosis Many of these studies will involve the use of novel mass spectrometric approaches. These studies should provide important information to our longterm goal of understanding the relationship between inflammation, lipoprotein metabolism and atherosclerosis.

高密度脂蛋白（HDL）在预防CVD中起关键作用。炎症是 在动脉粥样硬化的发病机理中的核心重要性。慢性炎症导致变化 在HDL [例如载脂蛋白A-L（APO A-L）和二氧化甲氧酮酶（PON1）降低，SAA增加 以及其他通过质谱法鉴定的新型蛋白质]。这些更改与 失去其动脉保护特性。炎症也可能导致促动源性变化 HDL。我们假设炎症引起的HDL的组成和功能变化 在炎症和动脉粥样硬化之间提供了重要的联系。我们还假设 HDL组成的变化可能是表明存在氧化损伤的生物标志物 和/或动脉粥样硬化在动脉壁的水平上。为了检验这些假设，我们计划 确定炎症（急性和慢性）如何影响HDL组成，功能和作用 小鼠动脉粥样硬化。接下来，我们将测试炎症减少的机制 动脉保护性HDL载脂蛋白Apo A-L和PON1，并增加了潜在的促进性 HDL中的载脂蛋白SAA。第三，我们将确定是否按 HDL中存在的炎症和抗炎蛋白的巨噬细胞影响起始 在高胆固醇血症的小鼠模型中，动脉粥样硬化的进展。最后，我们会的 确定慢性炎症是否改变了HDL中HDL的组成和功能特性是否改变 人类的方式与小鼠相似，以及HDL蛋白组成的变化是否是 氧化和/或动脉粥样硬化的标志物许多研究都将涉及使用新颖 质谱方法。这些研究应为我们的长期提供重要信息 了解炎症，脂蛋白代谢和 动脉粥样硬化。