title: Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK.
abstract: BACKGROUND
  Diabetic cardiomyopathy (DCM) suggests a direct cellular insult to myocardium. Hyperglycemia-induced oxidative stress and apoptosis have been implicated in the pathogenesis of DCM. NADPH oxidase is a major source of reactive oxygen species (ROS) generation in cardiomyocytes. Resveratrol, a naturally occurring polyphenol, has shown beneficial effects on some cardiovascular complications associated with diabetes.
  
  
  OBJECTIVE
  We aimed to examine the role of resveratrol on high glucose-induced NADPH oxidase-derived ROS production and cardiac apoptosis, together with modulation of protein signaling pathways in cardiomyocytes.
  
  
  METHODS
  Primary cultures of neonatal rat cardiomyocytes were exposed to 30 mmol/L high glucose with or without resveratrol. Cell viability, apoptosis, superoxide formation, NADPH oxidase activity and its subunits expression, antioxidant enzymes activities, as well as the potential regulatory molecules AMPK, Akt and GSK-3β were assessed in cardiac cells.
  
  
  RESULTS
  Elevated ROS production induced by 30 mmol/L high glucose was inhibited with the addition of resveratrol in primary cultured neonatal rat cardiomyocytes. Consistently, resveratrol markedly suppressed the increased activity of NADPH oxidase and Rac1, as well as the enhanced expression of p67(phox), p47(phox), and gp91(phox) induced by high glucose. Lipid peroxidation, SOD, catalase, GSH-px activity and GSH content was reversed in the presence of resveratrol. Moreover, the expression of pro-apoptotic protein Bax was down regulated while anti-apoptotic protein Bcl-2 was up regulated. And cardiac cell injury and apoptosis were markedly rescued by resveratrol. In addition, resveratrol significantly increased phosphorylation of AMP-activated protein kinase (AMPK) at Thr172 in cardiomyocytes exposed to high glucose. Compound C, the pharmacologic inhibitor of AMPK, could mostly abrogate roles of resveratrol on cardiomyocytes in high glucose. In contrast, Akt and GSK-3β were little influenced by resveratrol.
  
  
  CONCLUSIONS
  Our data demonstrated that resveratrol protected cardiomyocytes against high glucose-induced apoptosis through suppression NADPH oxidase-derived ROS generation and maintenance endogenous antioxidant defenses. And the protective effects of resveratrol are mostly mediated by AMPK related pathway.
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Guo
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China.
authors.forename: Hongguang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China. Electronic address: xywjl@163.com.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular, and Metabolic Disorders, Hubei University of Science and Technology, Xianning, China. Electronic address: xn_liuchao@163.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D005947:Glucose / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D002316:Cardiotonic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013267:Stilbenes; D051028:bcl-2-Associated X Protein; D000263:Adenylate Kinase; D020830:rac1 GTP-Binding Protein; D005947:Glucose; D000077185:Resveratrol
keywords: AMPK; Apoptosis; Cardiomyocytes; NADPH; ROS; Resveratrol