Impairment of Macrophage Cholesterol Efflux by Cholesterol Hydroperoxide Trafficking: Implications for Atherogenesis Under Oxidative Stress.
Impairment of Macrophage Cholesterol Efflux by Cholesterol Hydroperoxide Trafficking: Implications for Atherogenesis Under Oxidative Stress.
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DOI：
10.1161/atvbaha.115.306210
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Girotti AW
中科院分区：
文献类型：
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作者：
Korytowski W;Wawak K;Pabisz P;Schmitt JC;Chadwick AC;Sahoo D;Girotti AW
与心血管疾病相关的氧化应激可产生各种氧化脂质，包括胆固醇氧化物，如7-羟基过氧化氢(7-OOH)、7-羟基(7-OH)和7-酮(7=O)。与7=O和7-OH不同的是，7-OOH具有氧化还原活性，通过潜在的有毒自由基反应产生其他化合物。我们验证了这一新的假设，即在氧化应激条件下，类固醇合成急性调节(STAR)家族蛋白不仅将胆固醇运送到/进入血管巨噬细胞的线粒体，而且还可以诱导过氧化损伤，从而损害早期的胆固醇反向运输。用二丁酰cAMP刺激人单核细胞来源的THP-1巨噬细胞，可显著上调StarD1和ABCA1的表达。刺激前siRNA诱导的StarD1基因敲除(Kd)对StarD4没有影响，但减少了ABCA1的上调，将后者与StarD1的功能联系在一起。用C11-BODIPY和JC-1分别检测到，受刺激的StarD1-kd细胞线粒体内化7-OH的速度比未刺激的对照组慢，7-OH诱导的脂质过氧化和膜去极化作用也较少。暴露于7-OOH的主要功能后果是(I)线粒体CYP27A1活性丧失，(Ii)27-羟基胆固醇(27-OH)产量减少，以及(Iii)胆固醇输出ABCA1和Abcg1下调。与未受挑战的对照组相比，7-OHO刺激的巨噬细胞向apoA-I或高密度脂蛋白输出的胆固醇一直较少。StarD1介导的7-OOH转运也具有高度的细胞毒性，而7=O和7-OH的毒性最小。这项研究描述了一种先前未知的机制，即巨噬细胞胆固醇外流可以在氧化应激相关疾病(如慢性肥胖症和高血压)下丧失能力。我们的发现为巨噬细胞氧化还原损伤/功能障碍在动脉粥样硬化形成中的作用提供了新的见解。
Oxidative stress associated with cardiovascular disease can produce various oxidized lipids, including cholesterol oxides such as 7-hydroperoxide (7-OOH), 7-hydroxide (7-OH), and 7-ketone (7=O). Unlike 7=O and 7-OH, 7-OOH is redox-active, giving rise to the others via potentially toxic free radical reactions. We tested the novel hypothesis that under oxidative stress conditions, steroidogenic acute regulatory (StAR) family proteins not only deliver cholesterol to/into mitochondria of vascular macrophages, but also 7-OOH, which induces peroxidative damage that impairs early stage reverse cholesterol transport. Stimulation of human monocyte-derived THP-1 macrophages with dibutyryl-cAMP resulted in substantial upregulation of StarD1 and ABCA1. siRNA-induced StarD1 knockdown (kd) prior to stimulation had no effect on StarD4, but reduced ABCA1 upregulation, linking the latter to StarD1 functionality. Mitochondria in stimulated StarD1-kd cells internalized 7-OOH slower than non-stimulated controls and underwent less 7-OOH-induced lipid peroxidation and membrane depolarization, as probed with C11-BODIPY and JC-1, respectively. Major functional consequences of 7-OOH exposure were (i) loss of mitochondrial CYP27A1 activity, (ii) reduced 27-hydroxycholesterol (27-OH) output, and (iii) down-regulation of cholesterol-exporting ABCA1 and ABCG1. Consistently, 7-OOH-challenged macrophages exported less cholesterol to apoA-I or HDL than did non-challenged controls. StarD1-mediated 7-OOH transport was also found to be highly cytotoxic, whereas 7=O and 7-OH were minimally toxic. This study describes a previously unrecognized mechanism by which macrophage cholesterol efflux can be incapacitated under oxidative stress-linked disorders such as chronic obesity and hypertension. Our findings provide new insights into the role of macrophage redox damage/dysfunction in atherogenesis.