Hydrogen sulfide potentiates interleukin-1β-induced nitric oxide production via enhancement of extracellular signal-regulated kinase activation in rat vascular smooth muscle cells

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Abstract

Hydrogen sulfide (H2S) and nitric oxide (NO) are endogenously synthesized from l-cysteine and l-arginine, respectively. They might constitute a cooperative network to regulate their effects. In this study, we investigated whether H2S could affect NO production in rat vascular smooth muscle cells (VSMCs) stimulated with interleukin-1β (IL-1β). Although H2S by itself showed no effect on NO production, it augmented IL-β-induced NO production and this effect was associated with increased expression of inducible NO synthase (iNOS) and activation of nuclear factor (NF)-κB. IL-1β activated the extracellular signal-regulated kinase 1/2 (ERK1/2), and this activation was also enhanced by H2S. Inhibition of ERK1/2 activation by the selective inhibitor U0126 inhibited IL-1β-induced NF-κB activation, iNOS expression, and NO production either in the absence or presence of H2S. Our findings suggest that H2S enhances NO production and iNOS expression by potentiating IL-1β-induced NF-κB activation through a mechanism involving ERK1/2 signaling cascade in rat VSMCs.

Section snippets

Materials and methods

Materials. Rat recombinant IL-1β, NaHS, l-Cys, H2S gas, dl-propargylglycine (PAG), and HgCl2 were purchased from Sigma–Aldrich (St. Louis, MO). The mitogen-activated protein kinase (MAPK) inhibitors including U0126 for inhibition of an extracellular signal-regulated kinase 1/2 (ERK1/2), SP600125 for inhibition of a c-jun N-terminal kinase (JNK), and SB203580 for inhibition of a p38 MAPK were purchased from Calbiochem (San Diego, CA). Antibodies to iNOS and β-actin were purchased from Santa Cruz

Results

Rat VSMCs have been reported to respond to IL-1β alone with increased NO production and iNOS expression [26]. This response to IL-1β was used in this study as a model system to evaluate the possible effects of H2S on NO production and iNOS expression. NaHS was also used in this study as a source of H2S, because NaHS dissociates to Na+ and HS in solution, and then HS associates with H+ to continuously form stable H2S. It was reported that about one-third of the H2S existed as the gaseous form

Discussion

Besides vasodilating effect, NO has inhibitory effects on platelet aggregation, leukocyte adhesion, VSMC proliferation, and migration [15], [16], [17], [18], [19], [20], [21], [22], suggesting an important role of iNOS-derived NO in hypertension, atherosclerosis, and vascular remodeling. In this regard, the present study investigated whether H2S could affect NO production in rat VSMCs. Although the H2S donor NaHS by itself showed no effect on NO production, it augmented IL-1β-induced NO

Acknowledgment

This study was supported by the Korean Research Foundation Grant (KRF-2004-005-E00038).

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    These authors contributed equally to this work.

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