Abstract 15813: The Role of Endogenous and Exogenous Hydrogen Sulfide Following Pressure Overload Induced Hypertrophy and Heart Failure
Introduction: Hydrogen sulfide (H2S) is a potent signaling molecule that plays a critical role in cardiovascular homeostasis. Cystathionine gamma-lyase (CSE) produces H2S in the heart. The aim of this study was to investigate a role of both endogenous and exogenous H2S in pressure overload induced heart failure.
Methods: Male CSE Knockout (KO), wild type control (WT) mice, and male C57/BL6J mice (12-14 weeks old, n=15-20) were investigated. Baseline echocardiography was performed followed by transverse aortic constriction (TAC) to create pressure overload. In additional studies C57/BL6J mice received either vehicle (VEH) or a H2S donor. Mice received a novel, orally active H2S donor (NANT-1002) at a dose of 20 mg/kg/day delivered in the diet. Follow-up echocardiography was performed at 12 weeks following TAC surgery.
Results: CSE KO and WT mice showed equivalent hypertrophy after 3 weeks of TAC surgery, but CSE KO mice exhibited significantly exacerbated cardiac dysfunction. Left ventricular (LV) ejection fraction (EF) was 69% in VEH and 52% in CSE KO (p < 0.01). The ratio of heart and lung weight to tibia length in CSE KO mice were significantly greater as compared to WT mice (heart; 117.2 mg/cm vs. 91.3 mg/cm, p < 0.05 and lung; 95.8 mg/cm vs. 67.8 mg/cm, p < 0.05). Mice receiving NANT-1002 demonstrated similar hypertrophy after 3 weeks of TAC surgery, but significantly less LV cavity dilatation (LVEDD/LVESD; 3.73/2.73 mm vs. 4.67/3.99 mm, p < 0.01) and preservation of LVEF (54% vs. 32%, p < 0.001) compared to VEH mice. Treatment with NANT-1002 also attenuated pulmonary edema. The ratio of heart and lung weight to tibia length in VEH mice were significantly greater as compared to NANT-1002 mice (heart; 125.5 mg/cm vs. 94.9 mg/cm, p < 0.05 and lung; 120.4 mg/cm vs. 69.2 mg/cm, p < 0.001).
Conclusion: Our results indicate that endogenous H2S generated from CSE plays an important role to preserve cardiac contractile function in the setting of cardiac hypertrophy. Moreover, oral H2S therapy prevents the transition from compensated to decompensated cardiac hypertrophy and heart failure. These results suggest that administration of H2S releasing agents might be efficacious for the treatment of heart failure resulting from hypertension.
- © 2011 by American Heart Association, Inc.