title: Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1-Mediated Protein Kinase A/Uncoupling Protein 2 Pathway.
abstract: 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.
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Xiong
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Peijian
authors.initials: P
authors.lastname: Wang
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Ma
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Liuping
authors.initials: L
authors.lastname: Gong
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Sun
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Xunmei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: He
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China.
authors.forename: Zhencheng
authors.initials: Z
authors.lastname: Yan
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China. daoyanliu@yahoo.com zhuzm@yahoo.com.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Liu
authors.affiliation: From the Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Third Military Medical University, Chongqing Institute of Hypertension, Chongqing, China. daoyanliu@yahoo.com zhuzm@yahoo.com.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D003326:Coronary Circulation / Q000502:physiology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D018450:Disease Progression; D004562:Electrocardiography; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D014664:Vasodilation
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D009569:Nitric Oxide; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: TRPV1 protein, mouse; atherosclerosis; coronary disease; endothelium; mitochondria; reactive oxygen species; uncoupling protein 2