title: Atorvastatin inhibits myocardial cell apoptosis in a rat model with post-myocardial infarction heart failure by downregulating ER stress response.
abstract: OBJECTIVE
  To determine the effect of atorvastatin on rat heart failure after myocardial infarction and to investigate the underlying mechanism of atorvastatin-mediated myocardium protection.
  
  
  METHODS
  Thirty-eight rats were randomly divided into three groups: a heart failure model group (model group), a heart failure plus atorvastatin treatment group (atorvastatin group) and a sham-surgery group (control group). The rat heart failure model was established by ligation of the left anterior descending of coronary arteries (LADs). Changes in hemodynamics parameters were recorded after the final drug administration. Plasma brain natriuretic peptide (BNP) concentration was determined by enzyme-linked immunosorbent assay (ELISA). Histological diagnosis was achieved by hematoxylin and eosin (H&E) and Masson's trichrome staining. The expressions of 78 kDa glucose-regulated protein 78 (GRP78), caspase-12 and C/EBP homologous protein (CHOP, also known as GADD153) in myocardial cells and cultured cardiac myocytes were examined by Western blot. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used to evaluate myocardial cell apoptosis, and flow cytometry was performed to examine the cell apoptosis of cultured cardiac myocytes.
  
  
  RESULTS
  In the atorvastatin group, myocardial cells were lined up more orderly and myocardial fibrosis level was decreased compared to the model group. The expressions of GRP78, caspase-12 and CHOP in myocardial cells were decreased in atorvastatin group. Moreover, in the atorvastatin-treated group the cell apoptosis rate was reduced and the endoplasmic reticulum (ER) stress was activated in response to heart failure and angiotensin II (Ang II) stimulation.
  
  
  CONCLUSIONS
  By down-regulating GRP78, caspase-12 and CHOP expressions in myocardial cells in rat heart failure after myocardial infarction, atorvastatin treatment decreased the apoptosis of myocardial cells, suggesting the possible mechanism by which atorvastatin functions in protecting against heart failure.
authors.affiliation: Department of Internal Medicine and Cardiology, China-Japan Union Hospital, Norman Bethune College of Medicine, Jilin University, China.
authors.forename: Xian Jing
authors.initials: XJ
authors.lastname: Song
authors.forename: Chun Yan
authors.initials: CY
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
authors.forename: Melvin T
authors.initials: MT
authors.lastname: Korkor
authors.forename: Jie Yu
authors.initials: JY
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling / Q000379:methods; D009203:Myocardial Infarction / Q000150:complications*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D051742:Transcription Factor CHOP / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D000069059:Atorvastatin; D053454:Caspase 12; D006360:Heat-Shock Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020097:Natriuretic Peptide, Brain; D011758:Pyrroles; D051742:Transcription Factor CHOP; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP