title: The protective effect of trimetazidine on myocardial ischemia/reperfusion injury through activating AMPK and ERK signaling pathway.
abstract: BACKGROUND
  Trimetazidine (TMZ) is an anti-anginal drug that has been widely used in Europe and Asia. The TMZ can optimize energy metabolism via inhibition of long-chain 3-ketoacyl CoA thiolase (3-KAT) in the heart, with subsequent decrease in fatty acid oxidation and stimulation of glucose oxidation. However, the mechanism by which TMZ aids in cardioprotection against ischemic injury has not been characterized. AMP-activated protein kinase (AMPK) is an energy sensor that controls ATP supply from substrate metabolism and protects heart from energy stress. TMZ changes the cardiac AMP/ATP ratio by modulating fatty acid oxidation, thereby triggering AMPK signaling cascade that contributes to the protection of the heart from ischemia/reperfusion (I/R) injury.
  
  
  METHODS
  The mouse model of in vivo regional ischemia and reperfusion by the ligation of the left anterior descending coronary artery (LAD) was used for determination of myocardial infarction. The infarct size was compared between C57BL/6J WT mice and AMPK kinase dead (KD) transgenic mice with or without TMZ treatment. The ex vivo working heart perfusion system was used to monitor the effect of TMZ on glucose oxidation and fatty acid oxidation in the heart.
  
  
  RESULTS
  TMZ treatment significantly stimulates cardiac AMPK and extracellular signal-regulated kinase (ERK) signaling pathways (p<0.05 vs. vehicle group). The administration of TMZ reduces myocardial infarction size in WT C57BL/6J hearts, the reduction of myocardial infarction size by TMZ in AMPK KD hearts was significantly impaired versus WT hearts (p<0.05). Intriguingly, the administration of ERK inhibitor, PD98059, to AMPK KD mice abolished the cardioprotection of TMZ against I/R injury. The ex vivo working heart perfusion data demonstrated that TMZ treatment significantly activates AMPK signaling and modulating the substrate metabolism by shifting fatty acid oxidation to glucose oxidation during reperfusion, leading to reduction of oxidative stress in the I/R hearts. Therefore, both AMPK and ERK signaling pathways mediate the cardioprotection of TMZ against ischemic injury. The metabolic benefits of TMZ for angina patients could be due to the activation of energy sensor AMPK in the heart by TMZ administration.
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China; State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
authors.forename: Ji-Mei
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
authors.forename: Huanlei
authors.initials: H
authors.lastname: Huang
authors.affiliation: State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kuznicki
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Zheng
authors.affiliation: State University of New York at Buffalo, Buffalo, NY 14214, USA; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Sun
authors.affiliation: State University of New York at Buffalo, Buffalo, NY 14214, USA; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Nanhu
authors.initials: N
authors.lastname: Quan
authors.affiliation: State University of New York at Buffalo, Buffalo, NY 14214, USA; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China. Electronic address: guohuiming@vip.tom.cn.
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Guo
authors.affiliation: State University of New York at Buffalo, Buffalo, NY 14214, USA; Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China. Electronic address: zhuangjianzggd@aliyun.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, China. Electronic address: tanganqier@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D010084:Oxidation-Reduction; D014292:Trimetazidine / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D005227:Fatty Acids; D014665:Vasodilator Agents; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D014292:Trimetazidine
keywords: AMPK signaling; Cardioprotection; Ischemia/reperfusion; MAPK signaling; Trimetazidine