A tale of two gases: NO and H2S, foes or friends for life?

Abstract

Nitric oxide (NO) and hydrogen sulfide (H2S) have emerged as dominant redox regulators of numerous aspects of cellular and physiological functions within several organ systems included cardiovascular, immune and neurological tissues. Recent studies have begun to reveal that these two gaseous molecules may have redundant or overlapping pathophysiological functions often involving similar molecular targets. However, it remains less clear when and how NO and H2S may interact under biological and disease processes. In this graphical review, we discuss the current understanding of NO and H2S interactions and how they may functionally influence each other and what this may mean for biology and mechanisms of disease.

Keywords: Cardiovascular disease; Chemistry; Redox biology; Thiol; Vascular biology.

Fig. 1

Biosynthesis of NO and H₂S: NO and H₂S are enzymatically synthesized by three enzymes. H₂S is generated from oxidation of the substrates l-homocysteine, cystathionine, l-cysteine and 3-mercaptopyruvate through the enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). α-ketobutyrate, lanthionine, l-serine and pyruvate are the secondary products formed. NO is produced by three NOS isoforms neuronal, inducible and endothelial NO synthase (nNOS, iNOS and eNOS) that catalyze the oxidation of l-arginine to l-citrulline; Alternatively, production of H₂S occurs non-enzymatically from various storage forms of sulfur like thiosulfate, thiocysteine and sulfite; whereas NO is produced through reduction of nitrite/nitrate under low oxygen conditions.

Fig. 2

Common signaling pathways of H₂S and NO: H₂S and NO mediated vascular remodeling aspects through common pathway that include VEGF, HIF-1α, PI3K/AKT upregulated by H₂S. PI3K/AKT induces NOS/NO. H₂S directly effects NO through XO mediated nitrite. Both NO and H₂S are independently involved in upregulating cGMP; H₂S acts through K-ATP and PDE5, NO activates enzyme sGC to increase cGMP production that has downstream signaling effects of EC migration, proliferation and angiogenesis via PKG/Ras–Raf/ERK-p38 MAPK axis.

Fig. 3

NO and H₂S redox regulations and cytoprotection: (1) Reactive oxygen species are collectively formed from hydrogen peroxide (H₂O₂), peronynitrite (ONOO⁻) and superoxide radical (^•O₂⁻). Superoxide radical is formed from the mitochondrial complexes and uncoupling of eNOS, which further reacts with NO to form peroxynitrite. Nitrite/NO regulates NOX that upregulates H₂O₂ thereby contributing to ROS. (2) Both H₂S and nitrite/NO are involved in cytoprotection by inhibiting mitochondrial complexes I and IV and the intermediary component cytochrome C that generate ROS. (3) H₂S regulate NRF2 directly and via cGMP variant 8-SH-cGMP to reduce ROS production. Nrf2 also induces HO-1 mediated inhibition of ROS.

Fig. 4

Protein modifications mediated by NO and H₂S: (A) Oxidation of free thiol leads to form thiolate. A series of oxidation reactions can take place in the presence of increasing reactive nitrogen or oxygen species that can oxidize thiolate (protein-S-) to sulfenic acid (protein–SOH) further irreversibly oxidize to sulfinic (protein–SO₂H) and sulfonic acid (protein–SO₃H). (B) Reduction of disulfides forms thiols. A free thiol decoupled from disulfide can react with either H₂S to form –SSH group through persulfidation (sulfhydration) or may form nitrosothiol by reacting with dinitrogen trioxide (N₂O₃) that is formed from nitrite and a NO radical (NO^•). SNO formation occurs when NO reacts with a thiol and to form NO, likewise SNO can also release NO. SNO can be modified into glutathionylated thiol (protein–SSG) in presence of a GSH or can alternatively form nitrosoglutathione (GSNO). GSNO can further oxidize to form NO and GSH.

Fig. 5

Potential NO–H₂S chemical interactions: Radicals of NO (NO^•) and H₂S (HS^•) leads to formation of thionitrous acid (HSNO). HSNO formation can also occur from reaction between sodium nitroprusside (SNP) either with RSNO or H₂S. Alternatively the anionic form of H₂S, hydrosulfide ion (HS⁻) can react with a nitrosating species leading to form HSNO. Peroxynitrite reacts with H₂S to form sulfinyl nitrite (HSNO₂), which further dissociate into NO^• and HSO^•. HSNO can react with H2S to form nitroxyl (HNO), and HSNO upon hydration (H₂O) can lead to nitrite formation. HNO is also formed from l-arginine through a reaction of peroxynitrite. Finally, HNO can further dissociate into hydroxylamine on reacting with glutathione (GSH), releasing GSSG in this process, which can in turn react with HNO forming NO.