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.
Highlights
The development of systemic inflammatory response syndrome, sepsis and multiple organ dysfunction remain the common causes of morbidity and mortality in major burn injury, and it is generally accepted that the ischemic gut during shock phase may contribute to the development of sepsis and multiple organ dysfunction in burn patients [1,2,3]
This study demonstrates that valproic acid (VPA) treatment has protective effects on burn-induced gut epithelial barrier dysfunction
Our data support the hypothesis that major burn injury induces hypoxia-inducible factor-1α (HIF-1α) accumulation, which activates vascular endothelial growth factor (VEGF) and myosin light chain kinase (MLCK) gene transcription, leading to loss and redistribution of zonula occludens 1 (ZO-1) and the subsequent increase in gut epithelial barrier permeability
Summary
The development of systemic inflammatory response syndrome, sepsis and multiple organ dysfunction remain the common causes of morbidity and mortality in major burn injury, and it is generally accepted that the ischemic gut during shock phase may contribute to the development of sepsis and multiple organ dysfunction in burn patients [1,2,3]. HIF-1 is an important transcription factor regulating the utilization of oxygen, nutrients and plays critical roles in phsysiological adaptations to hypoxia [12,13] It is a heterodimer composed of an oxygen-inducible α subunit (HIF-1α) and an oxygenindependent subunit (HIF-1β) [14,15]. Efforts to attenuate the accumulation of HIF-1α may benefit burn patients who are at high risk of developing gut barrier dysfunction via the transcriptional repression of MLCK and VEGF expression. In this study, we aim to test the hypothesis that after major burn injury, VPA protects against the loss of ZO-1 through inhibiting the HIF-1αdependent regulation of MLCK and VEGF expression, thereby attenuating the gut epithelial barrier dysfunction. The expression of VEGF and MLCK are upregulated in Caco-2 cells stimulated with CoCl2, and VPA treatment prevents these changes
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