HDL, Inflammation and Atherosclerosis

高密度脂蛋白(HDL)在预防心血管疾病中起着关键作用。炎症是一种 在动脉粥样硬化发病机制中的中心重要性。慢性炎症导致变化 在高密度脂蛋白中[如载脂蛋白A-L(apoA-L)和对氧磷酶(PON1)降低，SAA增加 以及通过质谱学鉴定的其他新蛋白质]。这些更改与 丧失其抗动脉粥样硬化的性能。炎症也可能导致促动脉粥样硬化的改变 高密度脂蛋白。我们假设炎症引起的高密度脂蛋白的成分和功能改变 提供了炎症和动脉粥样硬化之间的重要联系。我们还假设 高密度脂蛋白组成的变化可能是指示氧化损伤存在的生物标志物 和/或动脉壁水平的动脉粥样硬化。为了检验这些假设，我们计划 确定炎症(急性和慢性)如何影响高密度脂蛋白的组成、功能和作用 小鼠的动脉粥样硬化形成。接下来，我们将测试炎症通过何种机制降低 动脉粥样硬化保护的高密度脂蛋白载脂蛋白A-L和PON1，并增加潜在的致动脉粥样硬化 高密度脂蛋白中的载脂蛋白SAA。第三，我们将通过以下方式确定局部过度表达 巨噬细胞中存在的炎症和抗炎蛋白影响高密度脂蛋白的启动 和/或高胆固醇血症小鼠模型中动脉粥样硬化的进展。最后，我们会 确定慢性炎症是否改变了高密度脂蛋白的组成和功能特性 人类的方式类似于小鼠，以及高密度脂蛋白组成的变化是否 氧化和/或动脉粥样硬化的标记物许多这些研究将涉及使用新的 质谱学方法。这些研究应该为我们的长期发展提供重要的信息 目的了解炎症、脂蛋白代谢和炎症之间的关系 动脉硬化。

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.