8-SH-cGMP endogenously formed from 8-nitro-cGMP as a second messenger of hydrogen sulfide

Abstract

An emerging aspect of redox signaling is the signaling pathway mediated by electrophilic metabolites, such as nitrated cyclic nucleotide (e.g., 8-nitroguanosine 3′,5′-cyclic monophosphate [8-nitro-cGMP]), generated via reactions of inflammatory-related enzymes, reactive oxygen species (ROS), nitric oxide (NO), and secondary products. Here we report that enzymatically generated hydrogen sulfide anion (HS−) regulates the metabolism and signaling actions of various electrophiles. HS− reacts with electrophiles most typically 8-nitro-cGMP via direct sulfhydration to form a unique second messenger of hydrogen sulfide, 8-SH-cGMP, which may eventually modulate cellular redox signaling. The relevance of this reaction is reinforced by the significant levels of 8-SH-cGMP formation in various mammalian cells in culture and tissues. In fact, 8-SH-cGMP can activate a classical cGMP-dependent protein kinase and is resistant to degradation by phosphodiestrases. Meanwhile, 8-SH-cGMP possesses a quite unique chemical property as a potent nucleophile, which was not expressed by its native cGMP. 8-SH-cGMP can bind reversibly with various protein sulfhydryls under oxidative condition via Cys-S-S-guanylation, which may affect physiological functions of various cellular and extracellular proteins, enzymes, and membrane channel/transport proteins, etc. Moreover, 8-SH-cGMP is readily decomposed to cGMP by ROS through oxidative desulfhydration. Another striking feature of 8-SH-cGMP is that its sulfhydryl moiety is transferred partly to protein Cys residues and much effectively to reactive electrophiles to form the same product with free HS−. The present study reveals HS−-induced electrophile sulfhydration and generate a novel second messenger for hydrogen sulfide, 8-SH-cGMP. 8-SH-cGMP may thus regulate redox-mediated cellular signaling mediated by hydrogen sulfide.