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.

Exogenous Hydrogen Sulfide Protects against Doxorubicin-Induced Inflammation and Cytotoxicity by Inhibiting p38MAPK/NFκB Pathway in H9c2 Cardiac Cells

“…More recently, we have demonstrated the cardioprotective effect of exogenous H 2 S against chemical hypoxia-induced insult by inhibiting oxidative stress and enhancing heat shock protein 90 (HSP90) expression [19,20]. Notably, the effects of H 2 S on the DOX-induced cardiotoxicity have attracted attention due to its antioxidant and anti-inflammatory effects [14,18,19,20,22,23,24]. The findings from in vivo and in vitro studies showed that DOX markedly reduces the endogenous H 2 S production in myocardium [25] or cardiomyocytes [7] and that exogenous H 2 S significantly improves the DOX-induced cardiac dysfunction [25] or cardiomyocyte injury [7] by its antioxidant effect.…”

“…The findings from in vivo and in vitro studies showed that DOX markedly reduces the endogenous H 2 S production in myocardium [25] or cardiomyocytes [7] and that exogenous H 2 S significantly improves the DOX-induced cardiac dysfunction [25] or cardiomyocyte injury [7] by its antioxidant effect. Furthermore, exogenous H 2 S attenuates the chemical hypoxia-induced inflammatory response in HaCaT cells [22] or PC12 cells [23] and ameliorates lipopolysaccharide (LPS)-triggered inflammation in microglia and astrocytes [24]. However, to our knowledge, no work has been focused on the protective effect of exogenous H 2 S against the DOX-induced inflammation and its mechanisms.…”

“…However, to our knowledge, no work has been focused on the protective effect of exogenous H 2 S against the DOX-induced inflammation and its mechanisms. Based on our recent studies [7,10,22,23] and others [24,25], the present study aimed to investigate whether exogenous H 2 S pretreatment can produce anti-inflammatory effects and explore the potential relation of these effects to inhibition of p38 MAPK/NF-κB pathway in the DOX-treated H9c2 cardiac cells [7]. …”

Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation

“…The generation of ROS may trigger multiple biological process, including apoptosis and programmed cell death (27). In a previous study on apoptosis caused by ultraviolet A (UVA) light, it was demonstrated that UVA triggers ROS-mediated apoptosis (27).…”

“…In a previous study on apoptosis caused by ultraviolet A (UVA) light, it was demonstrated that UVA triggers ROS-mediated apoptosis (27). In addition, the authors hypothesized that singlet oxygen is the dominant ROS.…”