Hydrogen sulfide protected gastric epithelial cell from ischemia/reperfusion injury by Keap1 s-sulfhydration, MAPK dependent anti-apoptosis and NF-κB dependent anti-inflammation pathway

Abstract

Hydrogen sulfide (H2S) has been proposed as a novel gas-transmittter, which plays multiple physiological and pathological functions in various body systems, including gastrointestinal tract. The present study was undertaken to investigate the effects and mechanisms of H2S pharmacological preconditioning on gastric epithelial cells ischemia-reperfusion (I/R) injury. We report here that sodium hydrosulfide (NaHS), an H2S donor, concentration-dependently suppressed I/R-induced cellular injury and apoptotic cell death. This protection effect was also confirmed by endogenous over-producing H2S. Furthermore, NaHS also prevented I/R-induced oxidative stress and inflammatory responses, evidenced by increases in GSH level, decreases in MDA contents, reactive oxygen species generation and secretions of NO, IL-6 and TNF-α. NaHS also prevented I/R-induced p38- and c-Jun NH2-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation. H2S also induced Keap1 s-sulfhydration, and further Keap1/Nrf2 disassociation and Nrf2 activation. H2S exerted its protective effect through reactive oxygen species clearance, inhibition of p38 and JNK dependent cell apoptosis and NF-κB dependent inflammation pathway. Our results provide evidence that H2S may have potential therapeutic value in acute gastric mucosal lesion, which is often caused by ischemia/reperfusion.

Keywords: H(2)S; Keap1; NF-κB; Oxidative stress; s-Sulfhydration.