Modification of HDL and Macrophage Function in Atherosclerosis

动脉粥样硬化性心血管疾病死亡率的一个主要因素是动脉粥样硬化性心血管疾病的形成和扩展。 病变内的坏死核心，当正常进行巨噬细胞增生时出现 （凋亡细胞的吞噬作用）不能清除凋亡细胞，而是经历继发性坏死。这 该项目旨在阐明两个家族的脂质，异evuglandins（IsoLG）和N- 酰基乙醇酰胺（NAE），可能通过HDL相互作用，改变巨噬细胞的功能， 以及Nape-pld的作用，Nape-pld是一种催化NAE形成和NAE降解的酶， 异LG加合物。我们假设在正常情况下，HDL促进巨噬细胞的能力， 通过1）接受巨噬细胞在吞噬过程中摄取的胆固醇来进行巨噬细胞吞噬作用， 2）将NAE前体递送至巨噬细胞，巨噬细胞使用它们的Nape-pld来水解这些NAE前体。 NAE的前体，其可以促进红细胞增多症所需的基因表达。我们假设， 在促进动脉粥样硬化的条件下，HDL被IsoLG修饰，IsoLG通过1） 抑制HDL接受胆固醇的能力和2）产生由模式识别识别的配体 驱动巨噬细胞成为促炎表型的受体， 细胞因子和低表达的蛋白质所需的红细胞。因此，HDL的IsoLG修饰和 Nape-pld表达的降低联合收割机抑制巨噬细胞的吞噬能力，导致 坏死核心的形成和扩张，其产生脆弱的动脉粥样硬化斑块。 我们将测试这个假设如下： 目的1将确定在胆固醇流出过程中对胆固醇流出至关重要的apoAI赖氨酸残基是否被异evuglandin修饰。 动脉粥样硬化的发展。 目的2将阐明脂二羰基修饰HDL增强炎症反应的机制， 并确定这些改变是否有助于减少巨噬细胞。 目的3探讨巨噬细胞Nape-pld基因缺失对动脉粥样硬化及巨噬细胞的影响 细胞增殖能力。

A major factor in mortality from atherosclerotic cardiovascular disease is the formation and expansion of necrotic cores within lesions, which arise when macrophages that normally carry out efferocytosis (phagocytosis of apoptotic cells) fail to clear apoptotic cells and instead undergo secondary necrosis. This project seeks to elucidate the contribution of two families of lipids, isolevuglandins (IsoLG) and N- acylethanolamides (NAEs), that potentially interact through HDL to altered macrophage efferocytic function, as well as the role of Nape-pld, an enzyme that catalyzes both the formation of NAEs and the degradation of the IsoLG adducts. We hypothesize that under normal conditions HDL promotes the ability of macrophages to carry out efferocytosis by 1) accepting the cholesterol that macrophages take up during phagocytosis of apoptotic cells and 2) delivering NAE precursors to macrophages which use their Nape-pld to hydrolyze these precursors to NAEs which can promote expression of genes needed for efferocytosis. We hypothesize that in conditions that promote atherosclerosis, HDL becomes modified by IsoLG which retards efferocytosis by 1) inhibiting HDL's ability to accept cholesterol and 2) creating ligands recognized by pattern recognition receptors that drive macrophages to a pro-inflammatory phenotype with high expression of inflammatory cytokines and low expression of proteins needed for efferocytosis. Thus, IsoLG modification of HDL and reduced Nape-pld expression combine to suppress the efferocytic capacity of macrophages, leading to the formation and expansion of necrotic cores which create vulnerable atherosclerotic plaques. We will test this hypothesis as follows: Aim 1 will determine if apoAI lysine residues critical to cholesterol efflux are modified by isolevuglandins during development of atherosclerosis. Aim 2 will elucidate the mechanisms whereby HDL modified by lipid dicarbonyls potentiate inflammation in macrophages and determine if these alterations contribute to reduced efferocytosis. Aim 3 will determine the effects of macrophage Nape-pld deletion on atherosclerosis and macrophage efferocytic capacity.