Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro
Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro
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DOI：
10.1172/jci5549
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发表时间：
1999-06-01
影响因子：
15.9
通讯作者：
Hazen, SL
中科院分区：
文献类型：
--
作者：
Podrez, EA;Schmitt, D;Hazen, SL
氧化的低密度脂蛋白与动脉粥样硬化有关；然而，体内将低密度脂蛋白转化为致动脉粥样硬化的途径尚未建立。活性氮的产生可能是一个重要的途径，因为从人的动脉粥样硬化的主动脉中回收的低密度脂蛋白富含硝基酪氨酸。我们现在报道，单核细胞的MPO-H2O2-NO2-系统产生的活性氮物种将低密度脂蛋白转化为一种形式(NO2-LDL)，该形式被巨噬细胞贪婪地摄取和降解，导致大量胆固醇沉积和泡沫细胞形成，这是病变发展的关键步骤。低密度脂蛋白的孵化。对于分离的MPO，一个过氧化氢产生系统，以及一氧化氮代谢的主要最终产物亚硝酸盐(NO2-)，导致载脂蛋白B 100酪氨酸残基的硝化和启动低密度脂蛋白的脂质过氧化。低密度脂蛋白硝化和脂质过氧化的时间进程与获得高亲和力、浓度依赖和饱和的NO2-LDL与人单核细胞来源的巨噬细胞和小鼠腹膜巨噬细胞的结合是平行的。低密度脂蛋白的修饰和转化为高摄取形式是在没有游离金属离子的情况下发生的，需要NO2-，发生在生理水平的氯离子中，并被血红素毒物、过氧化氢酶和BHT抑制。巨噬细胞与NO2-低密度脂蛋白的结合是特异的，既不是由低密度脂蛋白受体介导的，也不是由A类清道夫受体I型介导的。巨噬细胞暴露于NO2-低密度脂蛋白可促进胆固醇酯合成、细胞内胆固醇和胆固醇酯蓄积以及泡沫细胞的形成。总而言之，这些结果确定MPO产生的活性氮物种是将低密度脂蛋白转化为致动脉粥样硬化形式的一种生理上可信的途径。
Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL. with isolated MPO, an H2O2-generating system, and nitrite (NO2-)- a major end-product of NO metabolism-resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and Lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2-, occurred at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.