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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
Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation
Arterioscler Thromb Vasc Biol. 2016 Apr 28;36(6) :1090-100
PMID: 27127201    PMCID: PMC4882253    URL: http://www.ncbi.nlm.nih.gov/pubmed/27127201
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OBJECTIVE: 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) serves as signaling mediators for EC activation in early atherosclerosis. APPROACH AND RESULTS: 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 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, independently of the activities of nicotinamide adenine dinucleotide phosphate 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 activator protein-1 and inducing intercellular adhesion molecule-1 gene expression in vitro. Furthermore, we showed that mtROS inhibitor MitoTEMPO suppressed EC activation and aortic monocyte recruitment in apolipoprotein E knockout mice using intravital microscopy and flow cytometry methods. CONCLUSIONS: 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.
1524-4636 Li, Xinyuan Fang, Pu Li, Yafeng Kuo, Yin-Ming Andrews, Andrew J Nanayakkara, Gayani Johnson, Candice Fu, Hangfei Shan, Huimin Du, Fuyong Hoffman, Nicholas E Yu, Daohai Eguchi, Satoru Madesh, Muniswamy Koch, Walter J Sun, Jianxin Jiang, Xiaohua Wang, Hong Yang, Xiaofeng Journal article Arterioscler Thromb Vasc Biol. 2016 Apr 28. pii: ATVBAHA.115.306964.