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.
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.
Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Cheng
C
Guo
Center for Cancer Research, Medical school, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. Electronic address: liangfenlilily@163.com.
Fenli
F
Liang
Department of Pathology, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. Electronic address: walayats.ibms@kmu.edu.pk.
Walayat
W
Shah Masood
Department of Genetics and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Electronic address: yanxiaofei@mail.xjtu.edu.cn.
Xiaofei
X
Yan
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000166:cytology; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases; D006862:Hydrogen Sulfide
H(2)S; Keap1; NF-κB; Oxidative stress; s-Sulfhydration