Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy
Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy
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DOI：
10.1152/ajpheart.00584.2011
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发表时间：
2012-04-01
影响因子：
4.8
通讯作者：
Darley-Usmar, Victor M.
中科院分区：
文献类型：
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作者：
Higdon, Ashlee N.;Benavides, Gloria A.;Darley-Usmar, Victor M.
Higdon AN，Benavides GA，Chacko BK，Ouyang X，约翰逊MS，Landar A，Zhang J，Darley-Usmar VM.氯化血红素通过促进脂质过氧化导致内皮细胞线粒体功能障碍：自噬的保护作用。Am J Physiol Heart Circ Physiol 302：H1394-H1409，2012。首次发表于2012年1月13日; doi：10.1152/ajpheart.00584.2011。红细胞的溶血和肌肉损伤导致血红素蛋白肌红蛋白、血红蛋白和游离血红素释放到脉管系统中。血红素毒性的机制尚不清楚，但可能涉及脂质过氧化，我们假设这将导致内皮细胞线粒体损伤。为了测试这一点，我们使用牛主动脉内皮细胞（BAEC）的文化，并将其暴露于氯化血红素。氯化血红素导致线粒体功能障碍，自噬激活，线粒体自噬，并在高浓度下，细胞凋亡。为了检测氯化血红素是否诱导脂质过氧化和损伤蛋白质，我们使用生物素或Bodipy标记的花生四烯酸衍生物（Bt-AA，BD-AA）。我们发现，在用氯化血红素处理的细胞中，Bt-AA被氧化并与蛋白质形成加合物，这被α-生育酚抑制。血红素依赖性线粒体功能障碍也减弱α-生育酚。蛋白质巯基修饰和羰基形成发生在曝光，并没有被α-生育酚抑制。支持自噬的保护作用，抑制剂3-甲基腺嘌呤增强细胞死亡。这些数据表明，氯化血红素介导的细胞毒性，通过一种机制，涉及蛋白质修饰的氧化脂质和其他氧化剂，降低呼吸能力，并为自噬过程的保护作用。脂质过氧化的减弱可能能够保护内皮中的线粒体功能并保护细胞免受血红素依赖性毒性。
Higdon AN, Benavides GA, Chacko BK, Ouyang X, Johnson MS, Landar A, Zhang J, Darley-Usmar VM. Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy. Am J Physiol Heart Circ Physiol 302: H1394-H1409, 2012. First published January 13, 2012; doi: 10.1152/ajpheart.00584.2011.-The hemolysis of red blood cells and muscle damage results in the release of the heme proteins myoglobin, hemoglobin, and free heme into the vasculature. The mechanisms of heme toxicity are not clear but may involve lipid peroxidation, which we hypothesized would result in mitochondrial damage in endothelial cells. To test this, we used bovine aortic endothelial cells (BAEC) in culture and exposed them to hemin. Hemin led to mitochondrial dysfunction, activation of autophagy, mitophagy, and, at high concentrations, apoptosis. To detect whether hemin induced lipid peroxidation and damaged proteins, we used derivatives of arachidonic acid tagged with biotin or Bodipy (Bt-AA, BD-AA). We found that in cells treated with hemin, Bt-AA was oxidized and formed adducts with proteins, which were inhibited by alpha-tocopherol. Hemin-dependent mitochondrial dysfunction was also attenuated by alpha-tocopherol. Protein thiol modification and carbonyl formation occurred on exposure and was not inhibited by alpha-tocopherol. Supporting a protective role of autophagy, the inhibitor 3-methyladenine potentiated cell death. These data demonstrate that hemin mediates cytotoxicity through a mechanism which involves protein modification by oxidized lipids and other oxidants, decreased respiratory capacity, and a protective role for the autophagic process. Attenuation of lipid peroxidation may be able to preserve mitochondrial function in the endothelium and protect cells from heme-dependent toxicity.