Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation.
Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation.
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DOI：
10.1161/atvbaha.115.306964
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Yang X
中科院分区：
文献类型：
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作者：
Li X;Fang P;Li Y;Kuo YM;Andrews AJ;Nanayakkara G;Johnson C;Fu H;Shan H;Du F;Hoffman NE;Yu D;Eguchi S;Madesh M;Koch WJ;Sun J;Jiang X;Wang H;Yang X
高血压诱导的内皮细胞（EC）激活被认为是动脉粥样硬化形成中单核细胞募集的初始事件。然而，它仍然是不明确的机制是什么高血压诱导的EC激活。在这里，我们测试了一个新的假设，即线粒体活性氧（mtROS）作为早期动脉粥样硬化EC激活的信号介质。代谢组学和转录组学分析显示，在载脂蛋白E基因敲除（ApoE−/−）小鼠动脉粥样硬化早期，几种溶血磷脂酰胆碱（LPC）种类，如16：0，18：0和18：1，及其加工酶，包括Pla 2g 7和Pla 2g 4c，被显著诱导。利用电子自旋共振和流式细胞术，我们发现LPC 16：0，18：0和18：1诱导原代人主动脉内皮细胞（HAECs）的线粒体ROS，独立于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的活性。机制上，使用共聚焦显微镜和Seahorse XF线粒体分析仪，我们发现LPC通过独特的钙离子进入介导的质子泄漏和线粒体O2减少的增加诱导线粒体ROS。此外，我们发现mtROS有助于LPC诱导EC激活通过调节AP-1的核结合和诱导细胞间粘附分子1（ICAM-1）基因表达在体外。此外，我们使用活体显微镜和流式细胞术方法表明，mtROS抑制剂MitoTEMPO抑制了ApoE−/−小鼠的EC激活和主动脉单核细胞募集。ATP合成不偶联，但质子泄漏偶联的线粒体ROS增加介导LPC诱导的EC激活在早期动脉粥样硬化。这些结果表明，线粒体抗氧化剂是治疗血管炎症和心血管疾病的有希望的疗法。
Hyperlipidemia-induced endothelial cell (EC) activation is considered as an initial event responsible for monocyte recruitment in atherogenesis. However, it remains poorly defined what is the mechanism underlying hyperlipidemia-induced EC activation. Here we tested a novel hypothesis that mitochondrial reactive oxygen species (mtROS) serve as signaling mediators for EC activation in early atherosclerosis. Metabolomics and transcriptomics analyses revealed that several lysophosphatidylcholine (LPC) species, such as 16:0, 18:0 and 18:1, and their processing enzymes, including Pla2g7 and Pla2g4c, were significantly induced in the aortas of apolipoprotein E knockout (ApoE−/−) mice during early atherosclerosis. Using electron spin resonance and flow cytometry, we found that LPC 16:0, 18:0 and 18:1 induced mtROS in primary human aortic ECs (HAECs), independently of the activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Mechanistically, using confocal microscopy and Seahorse XF mitochondrial analyzer, we showed that LPC induced mtROS via unique calcium entry-mediated increase of proton leak and mitochondrial O2 reduction. In addition, we found that mtROS contributed to LPC-induced EC activation by regulating nuclear binding of AP-1 and inducing intercellular adhesion molecule 1 (ICAM-1) gene expression in vitro. Furthermore, we showed that mtROS inhibitor MitoTEMPO suppressed EC activation and aortic monocyte recruitment in ApoE−/− mice using intravital microscopy and flow cytometry methods. ATP synthesis-uncoupled, but proton leak-coupled mtROS increase mediates LPC-induced EC activation during early atherosclerosis. These results indicate that mitochondrial antioxidants are promising therapies for vascular inflammation and cardiovascular diseases.