title: [Salubrinal improves cardiac function in rats with heart failure post myocardial infarction through reducing endoplasmic reticulum stress-associated apoptosis].
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress plays an important role in ischemia-mediated cell death. The aim of the current study is to investigate the effects of salubrinal (Sal), a selective eIF2a dephosphorylation inhibitor, on heart failure rats and related mechanisms.
  
  
  METHODS
  Heart failure was induced by coronary artery ligation (MI) in adult male Sprague-Dawley rats. To ensure comparable MI sizes post coronary artery ligation on various groups, echocardiography examination was performed before and 30 minutes after ligation in MI groups. Then rats were randomly assigned to 4 groups: Sham group (n=12), MI group (n=10), MI plus vehicle injections group (DMSO group, n=12) and MI plus Sal injection group (Sal group, n=12). Sal (1 mg/kg) or DMSO was injected via the tail vein daily for the first 3 days (starting at 30 minutes after ligation of the left coronary artery), followed by subcutaneous injections twice per week for 8 weeks. Cardiac function was assessed by echocardiography and cell apoptosis assessed by flow cytometric analysis after 8 weeks. Protein and mRNA levels of ER stress markers were evaluated by immunohistochemistry and real time RT-PCR respectively.
  
  
  RESULTS
  Eight weeks later, LVEF was significantly higher, while LVESD and LVEDD values were significantly lower in Sal group compared to MI and DMSO groups (all P<0.05); LV/BW ratio was significantly higher in MI group than in Sham group ((2.30±0.40) mg/g vs.(1.78±0.31) mg/g, P<0.05), which was significantly reduced in Sal group ((1.88±0.25) mg/g), but not in DMSO group((2.25±0.36) mg/g, P<0.05 vs. MI). In addition, flow cytometric analysis showed that Sal treatment significantly reduced apoptosis but not necrosis in post MI. Immunohistochemistry and real time PCR analysis showed that the myocardial protein and mRNA expression of ER stress markers were significantly lower in Sal group than in MI group, myocardial caspase-12 expression was significantly upregulated in MI group and significantly reduced by Sal treatment.
  
  
  CONCLUSIONS
  Our results suggest that reduction of ER stress and myocardial apoptosis through inhibition of eIF2α dephosphorylation may serve as the potential mechanisms for the improved cardiac function and attenuated cardiac remodeling post Sal treatment in this heart failure rat model.
authors.affiliation: Department of Cardiology, Peace Hospital of People's Liberation Army, Shijiazhuang 050082, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: S Y
authors.initials: SY
authors.lastname: Qi
authors.forename: L S
authors.initials: LS
authors.lastname: Ru
authors.forename: C
authors.initials: C
authors.lastname: Ding
authors.forename: H J
authors.initials: HJ
authors.lastname: Wang
authors.forename: A Y
authors.initials: AY
authors.lastname: Li
authors.forename: B Y
authors.initials: BY
authors.lastname: Xu
authors.forename: G H
authors.initials: GH
authors.lastname: Zhang
authors.forename: D M
authors.initials: DM
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053454:Caspase 12 / Q000378:metabolism; D002934:Cinnamates / Q000494:pharmacology*; D004452:Echocardiography; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry; D006333:Heart Failure / Q000188:drug therapy*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D010766:Phosphorylation; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; C496827:salubrinal; C506443:Casp12 protein, rat; D053454:Caspase 12; D013890:Thiourea