title: Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model.
abstract: OBJECTIVE
  Burn-induced gut dysfunction plays an important role in the development of sepsis and multiple organ dysfunction. Emerging evidence suggests that hypoxia-inducible factor-1α (HIF-1α) is critical in paracellular barrier functions via regulating vascular endothelial growth factor (VEGF) and myosin light chain kinase (MLCK) expression. Previous studies have also demonstrated that histone deacetylase inhibitors (HDACIs) can repress HIF-1α. This study aims to examine whether valproic acid (VPA), a HDACI, protects against burn-induced gut barrier dysfunction via repressing HIF-1α-dependent upregulation of VEGF and MLCK expression.
  
  
  METHODS
  Rats were subjected to third degree 55% TBSA burns and treated with/ without VPA (300 mg/kg). Intestinal barrier dysfunction was evaluated by permeability of intestinal mucosa to fluorescein isothiocyanate (FITC)-dextran and histologic evaluation. Histone acetylation, tight junction protein zonula occludens 1 (ZO-1), VEGF, MLCK and HIF-1α were measured. In addition, CaCO2 cells were transfected with siRNA directed against HIF-1α and were stimulated with CoCl2 (1mM) for 24 hours with/without VPA (2mM) followed by analysis of HIF-1α, MLCK, VEGF and ZO-1.
  
  
  RESULTS
  Burn insults resulted in a significant increase in intestinal permeability and mucosal damage, accompanied by a significant reduction in histone acetylation, ZO-1, upregulation of VEGF, MLCK expression, and an increase in HIF-1α accumulation. VPA significantly attenuated the increase in intestinal permeability, mucosa damage, histone deacetylation and changes in ZO-1 expression. VPA also attenuated the increased VEGF, MLCK and HIF-1α protein levels. VPA reduced HIF-1α, MLCK and VEGF production and prevented ZO-1 loss in CoCl2-stimulated Caco-2 cells. Moreover, transfection of siRNA directed against HIF-1α led to inhibition of MLCK and VEGF production, accompanied by upregulation of ZO-1.
  
  
  CONCLUSIONS
  These results indicate that VPA can protect against burn-induced gut barrier dysfunction. These protective effects may be due to its inhibitory action on HIF-1α, leading to a reduction in intestinal VEGF and MLCK expression and minimizing ZO-1 degradation.
authors.affiliation: Laboratory of Shock and Organ Dysfunction, Burns Institute, the First Hospital Affiliated to the People's Liberation Army General Hospital, Beijing, China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Luo
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Du
authors.forename: Zhi-Long
authors.initials: ZL
authors.lastname: Lin
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Lv
authors.forename: Jiang-Yang
authors.initials: JY
authors.lastname: Lu
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Pi
authors.forename: Sen
authors.initials: S
authors.lastname: Hu
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Sheng
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002056:Burns / Q000150:complications*; D018938:Caco-2 Cells; D004195:Disease Models, Animal; D005759:Gastroenteritis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D014635:Valproic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020011:Protective Agents; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; D014635:Valproic Acid; D009219:Myosin-Light-Chain Kinase