Modification of HDL and Macrophage Function in Atherosclerosis

动脉粥样硬化性心血管疾病死亡的一个主要因素是血管的形成和扩张 皮损内的坏死核，当通常执行胞吐作用的巨噬细胞出现时 (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脂类家族的贡献，异uglandins(IsoLG)和N- 酰乙醇胺(NAE)，它可能通过高密度脂蛋白相互作用改变巨噬细胞的泡沫化功能，如 以及nape-pld的作用，nape-pld是一种催化NAE的形成和降解的酶 IsoLG加合物。我们假设，在正常情况下，高密度脂蛋白促进巨噬细胞 通过1)接受巨噬细胞在吞噬过程中摄取的胆固醇来进行吞噬 2)将NAE前体递送给巨噬细胞，巨噬细胞使用其NAPE-PLD来水解这些 NAE的前体，可以促进胞吐所需基因的表达。我们假设在 促进动脉粥样硬化的条件，高密度脂蛋白被IsoLG修饰，它可以延缓胞吐作用1) 抑制高密度脂蛋白接受胆固醇的能力和2)产生模式识别识别的配体 驱动巨噬细胞向高表达炎性细胞的促炎表型转变的受体 细胞因子和胞吐所需蛋白质的低表达。因此，高密度脂蛋白和高密度脂蛋白的等值修饰 NAPE-PLD表达减少会抑制巨噬细胞的吞噬能力，导致 坏死核的形成和扩张，形成脆弱的动脉粥样硬化斑块。 我们将对这一假设进行如下检验： 目标1将确定对于胆固醇外流至关重要的ApoAI赖氨酸残基是否被异uglandins修饰 动脉粥样硬化的发展。 目的2阐明脂质二羰基修饰的高密度脂蛋白增强炎症反应的机制。 并确定这些变化是否有助于减少泡沫化作用。 目的3确定巨噬细胞nAPE-PLD缺失对动脉粥样硬化和巨噬细胞的影响 泡沫化能力。

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.