title: ROCK-dependent ATP5D modulation contributes to the protection of notoginsenoside NR1 against ischemia-reperfusion-induced myocardial injury.
abstract: Cardiac ischemia-reperfusion (I/R) injury remains a challenge for clinicians, which initiates with energy metabolism disorder. The present study was designed to investigate the protective effect of notoginsenoside R1 (NR1) on I/R-induced cardiac injury and underlying mechanism. Male Sprague-Dawley rats were subjected to 30-min occlusion of the left coronary anterior descending artery followed by reperfusion with or without NR1 pretreatment (5 mg·kg(-1)·h(-1)). In vitro, H9c2 cells were cultured under oxygen and glucose deprivation/reoxygenation conditions after NR1 (0.1 mM), Rho kinase (ROCK) inhibitor Y-27632 (10 μM), or RhoA/ROCK activator U-46619 (10 nM) administration. Myocardial infarct size, myocardial histology, and cardiac function were evaluated. Myofibril and mitochondria morphology were observed by transmission electron microscopy. F-actin and apoptosis were determined by immunofluorescence and TUNEL staining. ATP and AMP content were assessed by ELISA. Phosphorylated-AMP-activated protein kinase, ATP synthase subunits, apoptosis-related molecules, and the level and activity of ROCK were determined by Western blot analysis. We found that NR1 pretreatment ameliorated myocardial infarction, histological injury, and cardiac function induced by I/R. Furthermore, similar to the effect of Y-27632, NR1 improved H9c2 cell viability, maintained actin skeleton and mitochondria morphology, and attenuated apoptosis induced by oxygen and glucose deprivation/reoxygenation. Importantly, NR1 prevented energy abnormity, inhibited the expression and activation of ROCK, and restored the expression of the mitochondrial ATP synthase δ-subunit both in vivo and in vitro, whereas U-46619 suppressed the effect of NR1. These results prove NR1 as an agent able to prevent I/R-induced energy metabolism disorder via inhibiting ROCK and enhancing mitochondrial ATP synthase δ-subunits, which at least partially contributes to its protection against cardiac I/R injury.
authors.affiliation: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: He
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Chun-Shui
authors.initials: CS
authors.lastname: Pan
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Yuan-Chen
authors.initials: YC
authors.lastname: Cui
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Bai-He
authors.initials: BH
authors.lastname: Hu
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chang
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Mao
authors.affiliation: Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China;
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Fan
authors.affiliation: Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China; Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China; Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China; and Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China hanjingyan@bjmu.edu.cn.
authors.forename: Jing-Yan
authors.initials: JY
authors.lastname: Han
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D004791:Enzyme Inhibitors / Q000494:pharmacology; D036145:Ginsenosides / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D000577:Amides; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D036145:Ginsenosides; D011725:Pyridines; C108830:Y 27632; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000255:Adenosine Triphosphate; D054460:rho-Associated Kinases; C072936:notoginsenoside R1
keywords: Rho kinase; apoptosis; energy deficit; inhibition; myocardium ischemia-reperfusion injury; notoginsenoside R1