Histone deacetylase inhibitors protect endothelial glycocalyx via suppressing hypoxia-inducible factor-1α–induced overexpression of matrix metalloproteinase 9 during hemorrhagic shock

BACKGROUND: Hemorrhagic shock (HS) induces severe vascular leakage, often resulting in multiple organ dysfunction, making it a critical medical challenge. The vascular endothelial glycocalyx (vEG), which covers the endothelial surface of the blood vessels, plays a critical role in maintaining the vascular barrier function. Protection of vEG offers novel therapeutic opportunities to improve clinical symptoms in patients with HS. Valproic acid (VPA) and tubastatin A (Tub A), as histone deacetylase inhibitors, have been found to have strong prosurvival effects in animal models with HS, but their impact on the shedding of vEG is still unknown during HS. The purpose of this study is to determine the comparative therapeutic effects of Tub A and VPA in protecting vEG during HS by suppressing hypoxia-inducible factor-1α (HIF-1α)/matrix metalloproteinase 9 (MMP-9) signaling. METHODS: This study constructed rat models of HS and human umbilical vein endothelial cell models of glucose-oxygen deprivation and conducted comparative studies on the protective effects and mechanisms of Tub A and VPA on vEG shedding induced by HS, thereby improving vascular leakage. RESULTS: Pulmonary-capillary permeability and the shedding of vEG were significantly increased after HS. Tub A and VPA reduced pulmonary-capillary permeability, inhibited the degradation of vEG, and downregulated the expression of HIF-1α and MMP-9 in rats with HS, and the effect of Tub A is better than VPA. Further in vitro investigations indicated that Tub A protected against endothelial glycocalyx degradation by suppressing HIF-1α-induced overexpression of MMP-9. CONCLUSION: Tub A attenuates the increased vascular permeability induced by HS by protecting vEG via inhibiting HIF-1α/MMP-9 signaling, with superior effects over VPA. These results highlight Tub A as a promising therapeutic candidate for protecting vascular integrity during HS.