title: Atorvastatin alleviates cardiomyocyte apoptosis by suppressing TRB3 induced by acute myocardial infarction and hypoxia.
abstract: OBJECTIVE
  TRB3 (tribbles 3), an apoptosis-regulated gene, increases during endoplasmic reticulum stress. Hypoxia can induce inflammatory mediators and apoptosis in cardiomyocytes. However, the expression of TRB3 in cardiomyocyte apoptosis under hypoxia is not thoroughly known. We investigated the regulation mechanism of TRB3 expression and apoptosis induced by hypoxia in cardiomyocytes.
  
  
  METHODS
  An in vivo model of acute myocardial infarction (AMI) was applied in adult Wistar rats to induce myocardial hypoxia. Rat neonatal cardiomyocytes were subjected to 2.5% O2to induce hypoxia.
  
  
  RESULTS
  The expression of TRB3 was evaluated in cultured rat neonatal cardiomyocytes subjected to hypoxia. Hypoxia significantly enhanced TRB3 protein and mRNA expression. Adding c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA (siRNA), tumor necrosis factor-α (TNF-α) antibody, and atorvastatin 30 minutes before hypoxia reversed the induction of TRB3 protein. A gel-shift assay showed the DNA-binding activity of growth arrest and DNA damage-inducible gene 153 (GADD153), which increased after hypoxia. Hypoxia increased, whereas the TRB3-mut plasmid, SP600125, and TNF-α antibody abolished the hypoxia-induced TRB3 promoter activity. Hypoxia increased the secretion of TNF-α from cardiomyocytes. Exogenous administration of TNF-α recombinant protein to the cardiomyocytes without hypoxia increased TRB3 protein expression, similar to that observed after hypoxia. Hypoxia-induced cardiomyocyte apoptosis is inhibited by TRB3 siRNA, the TNF-α antibody, and atorvastatin. Atorvastatin reduced the TRB3 expression and cardiomyocyte apoptosis induced by AMI. Hypoxia induces TRB3 through TNF-α, JNK, and the GADD153 pathway.
  
  
  CONCLUSIONS
  Treatment of atorvastatin inhibits the expression of TRB3 and cardiomyocyte apoptosis induced by AMI and hypoxia.
authors.affiliation: Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Cheng
authors.affiliation: Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Huey-Ming
authors.initials: HM
authors.lastname: Lo
authors.affiliation: Department of Medical Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Bao-Wei
authors.initials: BW
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of General Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Su-Kiat
authors.initials: SK
authors.lastname: Chua
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lu
authors.affiliation: Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. Electronic address: shyukg@ms12.hinet.net.
authors.forename: Kou-Gi
authors.initials: KG
authors.lastname: Shyu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000860:Hypoxia / Q000188:drug therapy* / Q000209:etiology; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C502443:Trib3 protein, rat; D000069059:Atorvastatin; D017346:Protein Serine-Threonine Kinases
keywords: AMI; TRB3; atorvastatin; cardiomyocytes; hypoxia