Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide

Abstract

Soluble guanylate cyclase (sGC) is a receptor for nitric oxide (NO). Binding of NO to ferrous (Fe2+) heme increases its catalytic activity, leading to the production of cGMP from GTP. Hydrogen sulfide (H2S) is a signalling molecule that exerts both direct and indirect anti-oxidant effects. In the present, study we aimed to determine whether H2S could regulate sGC redox state and affect its responsiveness to NO-releasing agents and sGC activators. Using cultured rat aortic smooth muscle cells, we observed that treatment with H2S augmented the response to the NO donor DEA/NO, while attenuating the response to the heme-independent activator BAY58-2667 that targets oxidized sGC. Similarly, overexpression of H2S-synthesizing enzyme cystathionine-γ lyase reduced the ability of BAY58-2667 to promote cGMP accumulation. In experiments with phenylephrine-constricted mouse aortic rings, treatment with rotenone (a compound that increases ROS production), caused a rightward shift of the DEA/NO concentration-response curve, an effect partially restored by H2S. When rings were pre-treated with H2S, the concentration-response curve to BAY 58-2667 shifted to the right. Using purified recombinant human sGC, we observed that treatment with H2S converted ferric to ferrous sGC enhancing NO-donor-stimulated sGC activity and reducing BAY 58-2667-triggered cGMP formation. The study identified an additional mechanism of cross-talk between the NO and H2S pathways at the level of redox regulation of sGC. Our results provide evidence that H2S reduces sGC heme Fe, thus, facilitating NO-mediated cellular signaling events.

Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre‐existing gastric ulcers

“…Similarly, CORM-2-mediated gastroprotection against aspirin-or ethanol-induced injury was reduced by co-treatment with ODQ or indomethacin respectively (Gomes et al, 2010;Magierowska et al, 2015;Magierowski et al, 2016a). Bucci et al (2012) and Zhou et al (2016) also demonstrated that H 2 S can stimulate NOmediated sGC activity, and therefore, H 2 S-mediated vasorelaxation has been considered to be cGMP-dependent, similar to the effect of CO. Moreover, H 2 S released from diallyl sulfide decreased nitrite production in intestinal epithelial cells (Fasolino et al, 2015).…”

“…() and Zhou et al . () also demonstrated that H 2 S can stimulate NO‐mediated sGC activity, and therefore, H 2 S‐mediated vasorelaxation has been considered to be cGMP‐dependent, similar to the effect of CO. Moreover, H 2 S released from diallyl sulfide decreased nitrite production in intestinal epithelial cells (Fasolino et al ., ).…”

Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling

“…In addition, Cyb5R3 may contribute to the maturation of sGC itself by participating in the heme insertion and reduction process and possibly protein folding 56 . Lastly, it has been reported that H 2 S can reduce oxidized sGC 57 ; however, it is unknown whether Cyb5R3 impacts this pathway. Future work dedicated to understanding the broad impact of Cyb5R3 on sGC-cGMP is warranted.…”

Regulation and role of endogenously produced hydrogen sulfide in angiogenesis

“…The ability of H 2 S to up regulate cGMP levels is, at least in part, due to the direct inhibition of PDE activity by H 2 S [70, 88] (Fig.2). Moreover, H 2 S converts sGC to its ferrous, NO-responsive form and further increases cGMP [90]. Furthermore, H 2 S production also activates the phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (Akt) pathway, leading to endothelial nitric oxide synthase (eNOS) phosphorylation and eNOS activation [70, 72, 91].…”