title: Inhibition of ROS-activated p38MAPK pathway is involved in the protective effect of H2S against chemical hypoxia-induced inflammation in PC12 cells.
abstract: We have demonstrated the neuroprotection of hydrogen sulfide (H2S) against chemical hypoxia-induced injury by inhibiting p38MAPK pathway. The present study attempts to evaluate the effect of H2S on chemical hypoxia-induced inflammation responses and its mechanisms in PC12 cells. We found that treatment of PC12 cells with cobalt chloride (CoCl2, a hypoxia mimetic agent) enhanced IL-6 secretion, nitric oxide (NO) generation and expression levels of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS). L-canavanine, a selective iNOS inhibitor, partly blocked CoCl2-induced cytotoxicity, apoptosis and mitochondrial insult. In addition, 7-Nitroindazole (7-NI), an inhibitor of nNOS, also partly attenuated the CoCl2-induced cytotoxicity. The inhibition of p38MAPK by SB203580 (a selective p38MAPK inhibitor) or genetic silencing of p38MAPK by RNAi (Si-p38) depressed not only CoCl2-induced iNOS expression, NO production, but also IL-6 secretion. In addition, N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, conferred a similar protective effect of SB203580 or Si-p38 against CoCl2-induced inflammatory responses. Importantly, pretreatment of PC12 cells with exogenous application of sodium hydrosulfide (a H2S donor, 400 μmol/l) for 30 min before exposure to CoCl2 markedly attenuated chemical hypoxia-stimulated iNOS and nNOS expression, NO generation and IL-6 secretion as well as p38MAPK phosphorylation in PC12 cells. Taken together, we demonstrated that p38MAPK-iNOS pathway contributes to chemical hypoxia-induced inflammation and that H2S produces an anti-inflammatory effect in chemical hypoxia-stimulated PC12 cells, which may be partly due to inhibition of ROS-activated p38MAPK-iNOS pathway.
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, No. 74, The Second Zhongshan Road, Guangzhou, 510080, Guangdong, People's Republic of China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lan
authors.forename: Wenming
authors.initials: W
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Hua
authors.forename: Dongdan
authors.initials: D
authors.lastname: Zheng
authors.forename: Runmin
authors.initials: R
authors.lastname: Guo
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.forename: Fen
authors.initials: F
authors.lastname: Hu
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Feng
authors.forename: Donghong
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D003035:Cobalt / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D000860:Hypoxia / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D003035:Cobalt; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; C018021:cobaltous chloride; D006862:Hydrogen Sulfide