title: Reduced endoplasmic reticulum stress might alter the course of heart failure via caspase-12 and JNK pathways.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress plays an important role in mediating ischemic heart cell death. The aim of this study was to investigate whether manipulation of a key factor of the ER stress pathway, eukaryotic translation initiation factor 2 subunit α (eIF2α), can change the natural history of heart failure (HF).
  
  
  METHODS
  HF was induced using coronary artery ligation in adult rats and a selective eIF2α dephosphorylation inhibitor, salubrinal (Sal), was used. Thirty minutes after ligation, rats were randomly assigned to 3 groups: myocardial infarction (MI) plus placebo injections (dimethyl sulfoxide; n = 12), MI plus Sal injection (Sal; n = 12), and MI (HF; n = 12). Hemodynamic parameters were examined. Hearts were harvested for apoptosis assessment after 8 weeks of Sal treatment by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labelling and flow cytometric analysis. Hearts were harvested to determine ER chaperones by Western analysis, real-time polymerase chain reaction and immunohistochemical analysis.
  
  
  RESULTS
  Cardiac function was significantly improved in Sal-treated rats. Apoptosis was reduced by Sal treatment. Glucose-regulated protein-78 and -94 were increased in HF but normalized by Sal treatment. HF caused a significant increase in eIF2α phosphorylation, which was further increased by Sal treatment, and caspase-12 and phospho-c-JUN NH2-terminal kinase were markedly increased in rats with HF alone but significantly reduced by Sal treatment.
  
  
  CONCLUSIONS
  Our results suggest that reduction of ER stress and myocardial apoptosis through inhibition of eIF2α dephosphorylation might alter the natural history of HF, which might provide a new approach for its treatment.
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang, Hebei, China; Department of Biochemistry and Molecular Biology, School of Basic Medicine, Laboratory of Medical Biotechnology of Hebei Province, Hebei Traditional Chinese Medical College, Shijiazhuang, Hebei, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang, Hebei, China.
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Qi
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang, Hebei, China.
authors.forename: Lei-Sheng
authors.initials: LS
authors.lastname: Ru
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang, Hebei, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Laboratory of Medical Biotechnology of Hebei Province, Hebei Traditional Chinese Medical College, Shijiazhuang, Hebei, China.
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang, Hebei, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medicine, Laboratory of Medical Biotechnology of Hebei Province, Hebei Traditional Chinese Medical College, Shijiazhuang, Hebei, China.
authors.forename: Ai-Ying
authors.initials: AY
authors.lastname: Li
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang, Hebei, China. Electronic address: slwangdm@126.com.
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053454:Caspase 12 / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D053454:Caspase 12