Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model.
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...
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doaj-d6dfc4bb97c14c7bb9f89cdf4f26f3292020-11-25T01:25:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7752310.1371/journal.pone.0077523Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model.Hong-Min LuoMing-Hua DuZhi-Long LinLin ZhangLi MaHuan WangWen YuYi LvJiang-Yang LuYu-Li PiSen HuZhi-Yong ShengOBJECTIVE: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.http://europepmc.org/articles/PMC3798300?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hong-Min Luo Ming-Hua Du Zhi-Long Lin Lin Zhang Li Ma Huan Wang Wen Yu Yi Lv Jiang-Yang Lu Yu-Li Pi Sen Hu Zhi-Yong Sheng |
spellingShingle |
Hong-Min Luo Ming-Hua Du Zhi-Long Lin Lin Zhang Li Ma Huan Wang Wen Yu Yi Lv Jiang-Yang Lu Yu-Li Pi Sen Hu Zhi-Yong Sheng Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. PLoS ONE |
author_facet |
Hong-Min Luo Ming-Hua Du Zhi-Long Lin Lin Zhang Li Ma Huan Wang Wen Yu Yi Lv Jiang-Yang Lu Yu-Li Pi Sen Hu Zhi-Yong Sheng |
author_sort |
Hong-Min Luo |
title |
Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. |
title_short |
Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. |
title_full |
Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. |
title_fullStr |
Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. |
title_full_unstemmed |
Valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. |
title_sort |
valproic acid treatment inhibits hypoxia-inducible factor 1α accumulation and protects against burn-induced gut barrier dysfunction in a rodent model. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3798300?pdf=render |
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