Valproic Acid Treatment Inhibits Hypoxia-Inducible Factor 1α Accumulation and Protects against Burn-Induced Gut Barrier Dysfunction in a Rodent Model

Abstract

ObjectiveBurn-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 paracelluar 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.MethodsRats were subjected to third degree 55% TBSA burns and treated with/ without VPA (300mg/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.ResultsBurn 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.ConclusionsThese 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.

Rhein inhibits lipopolysaccharide-induced intestinal injury during sepsis by blocking the toll-like receptor 4 nuclear factor-κB pathway

“…It has been suggested that sepsis is caused by an exaggerated inflammatory response, which may develop into septic shock and multiple organ dysfunction syndrome (3). During a severe infection, intestinal barrier dysfunction may lead to ischemia and hypoxia, both of which have an important role in the development of sepsis (4). In addition, emerging evidence suggests that the intestinal tract is not only a target of the inflammatory response, but may also be the starting point for multiple organ dysfunction (5).…”

Melatonin Protects the Esophageal Epithelial Barrier by Suppressing the Transcription, Expression and Activity of Myosin Light Chain Kinase Through ERK1/2 Signal Transduction

“…Prior studies have demonstrated that ERK phosphorylation contributes to the activation of the MLCK signaling pathway, which leads to barrier dysfunction in the vascular endothelium or intestinal epithelium [6]. Although MLCK is implicated in endothelial and epithelial barrier dysfunction [25,26], its specific role in the impairment of the esophageal epithelial barrier has not been reported. Our study provides direct evidence that ERK-mediated activation of MLCK plays a critical role in esophageal epithelial barrier dysfunction.…”

Alcohol Modulation of the Postburn Hepatic Response

“…Additionally, the HDAC inhibitor valproic acid (VPA), was beneficial in lethal burn models in rats and dogs. In rats, VPA treatment improved survival and gut barrier dysfunction and attenuated brain and cardiac injury [190,191]. In dogs, VPA improved survival, hemodynamics, and intestinal perfusion, and reduced circulating levels of the pro-inflammatory cytokine, TNF-α.…”