An Update on Hydrogen Sulfide and Nitric Oxide Interactions in the Cardiovascular System

Hydrogen sulfide (H2S) and nitric oxide (NO) are now recognized as important regulators in the cardiovascular system, although they were historically considered as toxic gases. As gaseous transmitters, H2S and NO share a wide range of physical properties and physiological functions: they penetrate into the membrane freely; they are endogenously produced by special enzymes, they stimulate endothelial cell angiogenesis, they regulate vascular tone, they protect against heart injury, and they regulate target protein activity via posttranslational modification. Growing evidence has determined that these two gases are not independent regulators but have substantial overlapping pathophysiological functions and signaling transduction pathways. H2S and NO not only affect each other’s biosynthesis but also produce novel species through chemical interaction. They play a regulatory role in the cardiovascular system involving similar signaling mechanisms or molecular targets. However, the natural precise mechanism of the interactions between H2S and NO remains unclear. In this review, we discuss the current understanding of individual and interactive regulatory functions of H2S and NO in biosynthesis, angiogenesis, vascular one, cardioprotection, and posttranslational modification, indicating the importance of their cross-talk in the cardiovascular system

Cystathionine γ-lyase S-sulfhydrates SIRT1 to attenuate myocardial death in isoprenaline-induced heart failure

ABSTRACTObjective: Hydrogen sulfide (H2S), the third gasotransmitter, plays a critical role in protecting against heart failure. Sirtuin-1 (SIRT1) is a highly conserved histone deacetylase that has a protective role in the treatment of heart failure by regulating the deacetylation of some functional proteins. This study investigates the interaction between SIRT1 and H2S in heart failure and the underlying mechanisms.Methods and Results: Using endogenous H2S-generating enzyme cystathionine γ-lyase (CSE) knockout mice, we found that CSE deficiency aggravated isoprenaline-induced cardiac injury. Treatment with H2S attenuated atrial natriuretic peptide level, brain natriuretic peptide level, improved cardiac function. Moreover, H2S treatment potentiated myocardial SIRT1 expression. Silencing CSE abolished intracellular SIRT1 expression. Furthermore, CSE/ H2S S-sulfhydrated SIRT1 at its zinc finger domains and augmented its zinc ion binding activity to stabilize the alpha-helix structure.Discussion: In conclusion, these results uncover that a novel mechanism that CSE/H2S S-sulfhydrated SIRT1 to prevent heart dysfunction through modulating its activity

Novel H2S-NO hybrid molecule (ZYZ-803) promoted synergistic effects against heart failure

Therapeutic strategies that increase hydrogen sulfide (H2S) or nitric oxide (NO) are cytoprotective in various models of cardiovascular injury. However, the nature of interaction between H2S and NO in heart failure and the underlying mechanisms for the protective effects remain undefined. The present study tested the cardioprotective effect of ZYZ-803, a novel synthetic H2S-NO hybrid molecule that decomposed to release H2S and NO. ZYZ-803 dose dependently improved left ventricular remodeling and preserved left ventricular function in the setting of isoprenaline-induced heart failure. The cardioprotective effect of ZYZ-803 is significantly more potent than that of H2S and/or NO donor alone. ZYZ-803 stimulated the expression of cystathionine γ-lyase (CSE) for H2S generation and the activity of endothelial NO synthase (eNOS) for NO production. Blocking CSE and/or eNOS suppressed ZYZ-803-induced H2S and NO production and cardioprotection. ZYZ-803 increased vascular endothelial growth factor (VEGF) concentration and cyclic guanosine 5′-monophosphate (cGMP) level. Moreover, ZYZ-803 upregulated the endogenous antioxidants, glutathione peroxidase (GPx) and heme oxygenase 1 (HO-1). These findings indicate that H2S and NO cooperatively attenuates left ventricular remodeling and dysfunction during the development of heart failure through VEGF/cGMP pathway and ZYZ-803 provide expanding insight into strategies for treatment of heart failure

Amelioration of mitochondrial dysfunction in heart failure through S-sulfhydration of Ca2+/calmodulin-dependent protein kinase II

Aims: Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in the development of heart failure and in the induction of myocardial mitochondrial injury. Recent evidence has shown that hydrogen sulfide (H2S), produced by the enzyme cystathionine γ-lyase (CSE), improves the cardiac function in heart failure. However, the cellular mechanisms for this remain largely unknown. The present study was conducted to determine the functional role of H2S in protecting against mitochondrial dysfunction in heart failure through the inhibition of CaMKII using wild type and CSE knockout mouse models. Results: Treatment with S-propyl-L-cysteine (SPRC) or sodium hydrosulfide (NaHS), modulators of blood H2S levels, attenuated the development of heart failure in animals, reduced lipid peroxidation, and preserved mitochondrial function. The inhibition CaMKII phosphorylation by SPRC and NaHS as demonstrated using both in vivo and in vitro models corresponded with the cardioprotective effects of these compounds. Interestingly, CaMKII activity was found to be elevated in CSE knockout (CSE-/-) mice as compared to wild type animals and the phosphorylation status of CaMKII appeared to relate to the severity of heart failure. Importantly, in wild type mice SPRC was found to promote S-sulfhydration of CaMKII leading to reduced activity of this protein, however, in CSE-/- mice S-sulfhydration was abolished following SPRC treatment. Innovation and conclusions: A novel mechanism depicting a role of S-sulfhydration in the regulation of CaMKII is presented. SPRC mediated S-sulfhydration of CaMKII was found to inhibit CAMKII activity and to preserve cardiovascular homeostasis. Keywords: Hydrogen Sulfide, Mitochondria, Heart Failure, Ca2+/calmodulin-dependent protein kinase II, S-sulfhydratio