Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide

Pharmacol Res. 2016 Sep;111:556-562. doi: 10.1016/j.phrs.2016.06.029. Epub 2016 Jul 1.

Abstract

Soluble guanylate cyclase (sGC) is a receptor for nitric oxide (NO). Binding of NO to ferrous (Fe(2+)) heme increases its catalytic activity, leading to the production of cGMP from GTP. Hydrogen sulfide (H2S) is a signaling 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 present 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.

Keywords: H(2)S; Nitric oxide; ROS; cGMP; sGC activators.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology
  • Benzoates / pharmacology
  • Cells, Cultured
  • Cystathionine gamma-Lyase / metabolism
  • Heme / metabolism*
  • Hydrogen Sulfide / pharmacology*
  • In Vitro Techniques
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Oxidation-Reduction
  • Phenylephrine
  • Quaternary Ammonium Compounds / pharmacology
  • Rats
  • Soluble Guanylyl Cyclase / metabolism*

Substances

  • Benzoates
  • Nitric Oxide Donors
  • Quaternary Ammonium Compounds
  • diethylammonium-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate
  • Phenylephrine
  • Nitric Oxide
  • BAY 58-2667
  • Heme
  • Cystathionine gamma-Lyase
  • Soluble Guanylyl Cyclase
  • Hydrogen Sulfide