title: Valproic acid-mediated myocardial protection of acute hemorrhagic rat via the BCL-2 pathway.
abstract: BACKGROUND
  Hemorrhage is a major cause of morbidity and mortality among trauma patients. The pathophysiologic changes following acute severe hemorrhage and tissue hypoxia lead to an imbalance of protein acetylation. Histone deacetylase inhibitors (HDACIs) were reported to restore the acetylation imbalance and serve as potential drugs for treating severe hemorrhage. However, the molecular mechanism of HDACI-mediated cytoprotection remains unclear. In this study, we examined the myocardial protective effects and respective mechanism of the HDACI valproic acid (VPA) administered during hemorrhagic and hypoxic stress in vivo and in vitro.
  
  
  METHODS
  In vivo, the therapeutic effect of VPA was evaluated in acute severe hemorrhagic rats, and the expressions of BCL-2 signal pathway molecules were observed in rat heart tissues. To explore the molecular mechanism of VPA-mediated myocardial protection, a cobalt chloride (CoCl2)-induced hypoxia model of rat H9c2 cardiomyoblasts was applied to mimic hypoxic injury raised by acute hemorrhage.
  
  
  RESULTS
  VPA administration significantly improved the 4-hour survival rate of hemorrhagic animals from 55% to 100% and protected H9c2 cells against CoCl2-induced hypoxic injury at a dose of between 12.5 μM and 100 μM. Increased expression of BCL-2 messenger RNA was observed following VPA treatment in the heart tissues of hemorrhagic rats (approximately 4.9-fold) and in H9c2 cells that survived CoCl2-induced hypoxia (approximately 4.9-fold). Western blot analysis showed a concomitant increase in BCL-2 protein expression and Akt phosphorylation following VPA treatment. The cytoprotective activity of VPA was diminished by triciribine-mediated inhibition of Akt activation and by silencing of BCL-2 gene expression.
  
  
  CONCLUSIONS
  These findings suggest that VPA protects myocardial cells from hemorrhagic and hypoxic stress through the Akt/BCL-2 survival pathway, indicating a potential use of HDACIs for acute severe hemorrhage treatment.
authors.affiliation: From the Beijing Institute of Transfusion Medicine (C.W., Y.W., Z.Q., Q.K., Y.W., X.W., M.H., W.L., Y.H., S.R., Q.Y.); and Beijing 307 Hospital (C.W.), Beijing, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Qiao
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Kuai
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuanlin
authors.initials: X
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.forename: Weijing
authors.initials: W
authors.lastname: Li
authors.forename: Yuezhong
authors.initials: Y
authors.lastname: He
authors.forename: Suping
authors.initials: S
authors.lastname: Ren
authors.forename: Qun
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006470:Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D007262:Infusions, Intravenous; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D012313:RNA / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: C000595707:BCL2 protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014635:Valproic Acid; D012313:RNA