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Introduction: Consensus has formed that hydrogen sulfide (H2S) has robust cytoprotective actions in multiple organ systems. The pro-survival actions and biological profiles of H2S are remarkably similar to those of nitric oxide (NO). Although there is recent evidence of cross-talk between H2S and NO, these molecules are thought to modulate independent signaling pathways. Methods/Results: Mice devoid of the key H2S producing enzyme, cystathionine gamma-lyase (CSE KO), exhibited impaired endothelial nitric oxide synthase (eNOS) function and diminished circulating nitrite (0.41 uM vs 0.73μM, p <0.05) nitrosylated protein (3.37nM vs 15.03nM, p <0.05), and cyclic GMP (9.3 vs 28.05pmol/ml, p <0.01) levels compared to wild-type (WT) mice. Further studies revealed that H2S therapy in CSE KO mice restored eNOS function and NO levels. eNOS KO mice and mice with phospho-dead eNOS (S1179A) were subjected to 45min of ischemia, followed by 24h of reperfusion. The H2S donor, Na2S (100μg/kg), or vehicle (0.9% NaCl) was administered 5min before reperfusion. There was no significant change in myocardial infarction in the H2S-treated group compared to the vehicle-treated group. Conclusion: These findings reveal that H2S modulates eNOS activity and nitric oxide signaling. Moreover, the inability of H2S therapy to protect eNOS dysfunctional mice against myocardial ischemia/reperfusion injury indicates that the cardioprotective actions of H2S are dependent on eNOS function and NO signaling. [Copyright &y& Elsevier]

Introduction: Hydrogen sulfide (H2S) is the endogenous signaling gasotransmitter, offering protective effects on oxidative stress including ischemia–reperfusion and hypertrophy/heart failure (HF). CSE is believed to be the major H2S-generating enzyme in the heart. Our previous study investigated that CSE KO mice are more susceptible to oxidative stress. NF-kappaB is a marker of cellular oxidative stress and its activation has been found to increase in ischemia–reperfusion and hypertrophy/HF. The purpose of the present study was to investigate the role of NF-kappaB in response to CSE. Methods/results: We found that both mRNA and protein levels of NF-kappaB-p65 were significantly increased in the heart tissues of CSE KO mice compared with control as they were judged by RT-qPCR and immunoblot, respectively. Interestingly, phosphorylation of p65 was increased (1.4 fold, p <0.05) in CSE KO mice. By utilizing electrophoretic mobility shift assay, we found increased NF-kappaB DNA binding activity in CSE KO mice compared to control. In addition, biomarkers of oxidative stress such as malondialdehyde (1.3 fold, p <0.05) and protein carbonyl (2 fold, p <0.01) formation were increased in heart tissues of CSE KO mice compared to wild type. Conclusion: Since we observed that the activation of NF-kappaB occurred in the heart tissues of CSE KO mice, our findings suggest that CSE may protect the heart from oxidative injury, such as that which occurs during ischemia–reperfusion, hypertrophy/HF. [Copyright &y& Elsevier]