Abstract 19206: Pressure Overload Induced Heart Failure Reduces Endogenous Hydrogen Sulfide (H2S) and Mitochondrial Respiratory Function but is Rescued by a Novel H2S Sulfide Donor
Introduction: Sustained hypertension induces cardiac hypertrophy and dysfunction with increased generation of reactive oxygen species (ROS) by the mitochondria and other cellular sources. Hydrogen sulfide (H2S) is a potent signaling molecule that has been shown to attenuate oxidant-mediated cardiac injury. We investigated the effects of hypertension-induced heart failure on endogenous H2S production, mitochondrial function, and left ventricular performance.
Methods: Transverse aortic constriction (TAC) was performed in male, C57BL/6J mice (n=15-20 per group). Mice received a novel, orally active H2S donor (SG-1002 at 20 mg/kg/day) delivered in the diet at 1 week prior to TAC. Follow-up echocardiography was performed up to 6 weeks. H2S and the stable metabolite - sulfane sulfur - were measured. Additionally, 8-isoprostane levels in the heart and myocardial mitochondrial respiratory function were also assessed following TAC.
Results: Control and SG-1002 treated mice exhibited equivalent hypertrophy (VEH; 1.35 mm vs. SG-1002; 1.34 mm) at 6 weeks following TAC, but SG-1002 mice exhibited significantly improved cardiac function (EF; 69% vs. 47%, p < 0.001). Interestingly, control mice exhibited significantly lower H2S and sulfane sulfur levels in the blood and heart compared to sham mice at 6 weeks following TAC. Treatment with SG-1002 partially rescued H2S and sulfane sulfur levels in the blood and heart. Control mice exhibited higher 8-isoprostane levels in the heart compared to sham or SG-1002 treated mice at 6 weeks following TAC. At 6 weeks following TAC, myocardial mitochondrial respiratory function was also reduced, but rescued by SG-1002 diet.
Conclusion: Our results indicate that pressure overload induced hypertrophy attenuates endogenous H2S bioavailability as a result of increased oxidative stress and mitochondrial dysfunction. Restoring endogenous H2S with an oral H2S donor may be a potential treatment in the setting of hypertensive heart failure.
- Cardiac hypertrophy
- Experimental heart failure
- Mitochondrial energetics, heart failure, arrhythmias
- Oxidative stress
- © 2012 by American Heart Association, Inc.