Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway
Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway
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DOI：
10.1161/hypertensionaha.115.06223
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发表时间：
2016-02
期刊：
影响因子：
8.3
通讯作者：
Shiqiang Xiong;Peijian Wang;Liqun Ma;Peng Gao;Liuping Gong;Li Li-Li;Qiang Li;Fang Sun;Xunmei Zhou;Hong-bo He;Jing Chen;Zhencheng Yan;Daoyan Liu;Zhiming Zhu
中科院分区：
文献类型：
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作者：
Shiqiang Xiong;Peijian Wang;Liqun Ma;Peng Gao;Liuping Gong;Li Li-Li;Qiang Li;Fang Sun;Xunmei Zhou;Hong-bo He;Jing Chen;Zhencheng Yan;Daoyan Liu;Zhiming Zhu
由动脉粥样硬化引起的冠心病是全球心源性死亡的主要原因。线粒体是活性氧（ROS）的主要来源，线粒体呼吸链的氧化磷酸化缺陷有助于ROS的产生。解偶联蛋白2（UCP 2）是一种适应性抗氧化防御因子，可保护动脉粥样硬化中线粒体ROS诱导的内皮功能障碍。瞬时受体电位香草素1（TRPV 1）的激活可减轻血管功能障碍。因此，TRPV 1激活是否通过减轻内皮线粒体功能障碍和增强蛋白激酶A/UCP 2途径的活性来拮抗冠状动脉病变值得研究。ApoE−/−、ApoE−/−/TRPV 1 −/−和ApoE−/−/UCP 2 −/−小鼠喂食标准食物、高脂饮食（HFD）或HFD加0.01%辣椒素。HFD摄入严重损害了冠状动脉血管扩张和心肌灌注，缩短了ApoE−/−小鼠的生存时间。TRPV 1或UCP 2缺乏会加重HFD诱导的冠状动脉功能障碍，并与内皮细胞中ROS生成增加和一氧化氮生成减少有关。辣椒素激活TRPV 1通过蛋白激酶A磷酸化上调UCP 2表达，从而减轻内皮线粒体功能障碍并抑制线粒体ROS生成。在体内，饮食中补充辣椒素增强了冠状动脉舒张，延长了HFD喂养的ApoE−/−小鼠的生存时间。在缺乏TRPV 1或UCP 2基因的ApoE−/−小鼠中没有观察到这些效应。通过TRPV 1激活上调蛋白激酶A /UCP 2可改善冠状动脉功能障碍，并通过改善内皮线粒体功能障碍延长动脉粥样硬化小鼠的寿命。饮食中补充辣椒素可能是一种有希望的冠心病一级预防干预措施。
Coronary heart disease arising from atherosclerosis is a leading cause of cardiogenic death worldwide. Mitochondria are the principal source of reactive oxygen species (ROS), and defective oxidative phosphorylation by the mitochondrial respiratory chain contributes to ROS generation. Uncoupling protein 2 (UCP2), an adaptive antioxidant defense factor, protects against mitochondrial ROS-induced endothelial dysfunction in atherosclerosis. The activation of transient receptor potential vanilloid 1 (TRPV1) attenuates vascular dysfunction. Therefore, whether TRPV1 activation antagonizes coronary lesions by alleviating endothelial mitochondrial dysfunction and enhancing the activity of the protein kinase A/UCP2 pathway warrants examination. ApoE−/−, ApoE−/−/TRPV1−/−, and ApoE−/−/UCP2−/− mice were fed standard chow, a high-fat diet (HFD), or the HFD plus 0.01% capsaicin. HFD intake profoundly impaired coronary vasodilatation and myocardial perfusion and shortened the survival duration of ApoE−/− mice. TRPV1 or UCP2 deficiency exacerbated HFD-induced coronary dysfunction and was associated with increased ROS generation and reduced nitric oxide production in the endothelium. The activation of TRPV1 by capsaicin upregulated UCP2 expression via protein kinase A phosphorylation, thereby alleviating endothelial mitochondrial dysfunction and inhibiting mitochondrial ROS generation. In vivo, dietary capsaicin supplementation enhanced coronary relaxation and prolonged the survival duration of HFD-fed ApoE−/− mice. These effects were not observed in ApoE−/− mice lacking the TRPV1 or UCP2 gene. The upregulation of protein kinase A /UCP2 via TRPV1 activation ameliorates coronary dysfunction and prolongs the lifespan of atherosclerotic mice by ameliorating endothelial mitochondrial dysfunction. Dietary capsaicin supplementation may represent a promising intervention for the primary prevention of coronary heart disease.