Abstract 16631: Genetic Deficiency of the Hydrogen Sulfide H2S Enzyme, Cystathionine Gamma-lyase (CSE) Results in eNOS Uncoupling and Exacerbated Myocardial Injury: Evidence for Cross Talk Between NO and H2S Signaling
Introduction: Hydrogen sulfide (H2S) is formed in the heart and vasculature from cysteine via cystathionine γ-lyase (CSE). We have previously demonstrated that both endogenous and exogenous H2S protects against myocardial ischemia (MI) and reperfusion (R) injury and heart failure. We evaluated the effects of genetic deficiency of CSE on H2S-mediated cardioprotection following myocardial ischemia/reperfusion (MI/R).
Methods: H2S was measured using gas chromatography and chemiluminesence. CSE KO and wild-type (WT) mice were subjected to 45 min of MI and 24 hr of R. Myocardial area-at-risk (AAR) per left ventricle (LV), and infarct (INF) per AAR were measured. Nitrite and Bh4 levels were measured by HPLC. Western blot analysis was performed for myocardial p-eNOSser1177 and total eNOS.
Results: CSE KO mice exhibited significant reductions in H2S compared to WT mice. CSE KO mice displayed a significant (p < 0.01) increase in myocardial INF per AAR compared to WT (62 ± 2% vs. 42 ± 3%) following MI/R. MI/R injury in CSE KO mice was attenuated by 50% following acute H2S therapy. Myocardial eNOS phosphorylation (Ser1177) was significantly attenuated in the CSE KO mice indicating eNOS uncoupling. Furthermore, CSE KO mice displayed significant reductions in myocardial nitric oxide (NO) bioavailability (nitrite and nitrosothiols) compared to WT. The eNOS cofactor, tetrahydrobiopterin (Bh4), was significantly reduced in CSE KO mice compared to WT providing further evidence for eNOS dysregulation. Summary and
Conclusion: Genetic deficiency of CSE results in significant reductions in H2S bioavailability, attenuated eNOS function, and reduced NO bioavailability. Our data demonstrate the critical role of endogenous H2S on protection of the heart against MI/R injury and the regulation of NO production.
- © 2013 by American Heart Association, Inc.