Cooperative Interactions Between NO and H₂S: Chemistry, Biology, Physiology, Pathophysiology

The mutual interaction of sulfide and NO (also known as the "NO/H₂S cross-talk") has both chemical and biological foundations. With respect to the chemical aspects, the formation of an intermediary nitrosothiol was proposed after the reaction of NO and H₂S, which was initially attributed to the highly reactive and short-lived HSNO. Subsequent chemical studies focusing on the reactivity of aqueous sulfide solutions with nitrosothiols, peroxynitrite, and NO donors such as sodium nitroprusside revealed that the kinetics and reaction mechanisms are complex and only partially understood. Recent work in this area resulted in the rediscovery of a forgotten chemistry of S-N hybrid molecules, a class of compounds characterized more than half a century ago. Other lines of investigations revealed that the reaction of sulfide with NO or nitrosothiols under biologically relevant conditions leads to formation of three different classes of intermediates including ONSS^- (perthionitrite, nitrosopersulfide), Sx2 (polysulfides of different chain lengths), and ON(NO)SO3- (the NONOate SULFI/NO); their generation contributes to NO scavenging, NO storage and transport, redox conversion of NO to HNO, and sulfane sulfur signaling. These reactions with sulfide are proposed to be of fundamental significance for NO signaling by modulating its bioactivity via conversion to new chemical entities with properties distinct from those of NO. The release of NO and H₂S from various stable or semistable chemical "pools" can contribute to the biological responses to NO and H₂S. With respect to the biological aspects, one level of interaction between NO and H₂S relates to their convergence on AKT PI3K signaling, in part due to the activation of PI3K by H₂S and in part due to the inhibition of phosphatase and tensin homolog (PTEN) by H₂S. These processes lead to increased intracellular PIP3 levels, which, in turn, lead to the activation of NO synthase due to a combination of phosphorylation and dephosphorylation of critical tyrosine residues. In addition, H₂S and NO signaling converge on various checkpoints of the guanylate cyclase/cGMP/protein kinase G; H₂S can reduce guanylate cyclase, thereby preventing its oxidative inactivation; H2S can inhibit phosphodiesterases, thereby prolonging the biological half-life of cGMP, and H₂S-derived polysulfides can activate protein kinase G. Moreover, H₂S can directly interact with NOS, resulting in its sulfhydrative activation and its stabilization in the physiological, dimeric state. In many experimental models, the protective or vascular effects of H₂S are diminished or are absent in the absence of functional eNOS, further underlining the critical importance of cooperative NO/H₂S interactions.