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.