Abstract 17903: Novel Esterase-Activated Hydrogen Sulfide Donors Attenuate Myocardial Ischemia/Reperfusion Injury
Background: Hydrogen sulfide (H2S) protects against acute myocardial ischemia/reperfusion (MI/R) injury and heart failure by ameliorating oxidative stress and attenuating cell death. A major limitation of currently available H2S donors is poor pharmacokinetics resulting in uncontrolled H2S release. BW-HP-102 is a novel H2S prodrug designed for sustained release of H2S upon catalysis by esterase. In preliminary studies, we observed sustained release of H2S in PBS solution with the presence of porcine liver esterase. We hypothesized that BW-HP-102 would be activated in vivo by endogenous esterase and ameliorate myocardial cell death following MI/R in a murine model.
Methods and Results: C57BL/6J male mice (10-12 weeks of age) were subjected to 45 min. of MI followed by 24 hr. of R. At reperfusion, animals received iHP (Control), BW-HP-102 (0.1 mg/kg, 0.5 mg/kg, and 1 mg/kg), or Na2S (50 μg/kg) by direct intracardiac (i.c.) injection. At 4 hours of R, plasma was collected for troponin-I measurements. Myocardial infarct size was reduced by 50% (p < 0.001 vs. Control) in mice treated with intermediate dose BW-HP-102 (0.5 mg/kg), 42% (p < 0.05 vs. Control) in mice treated with high dose BW-HP-102 (1 mg/kg), and 47% (p < 0.001 vs. Control) in mice treated with Na2S; whereas in mice treated with low dose BW-HP-102 (0.1 mg/kg), we did not observe any significant protection. Circulating troponin-I level was also reduced by 42% (p < 0.001 vs Control) in mice treated with BW-HP-102 (0.5 mg/kg), 32% (p < 0.05 vs. Control) in mice treated with BW-HP-102 (1 mg/kg), 41% (p < 0.001 vs. Control) in mice treated with Na2S (50 μg/kg).
Conclusions: BW-HP-102 significantly attenuates MI/R injury in a dose dependent manner, and its cardioprotective effect is comparable to a traditional H2S donor, Na2S. Experiments are currently underway to further define the pharmacokinetics, mechanisms of action, and safety profile of this H2S prodrug.
Author Disclosures: Z. Li: None. C.L. Organ: None. Y. Zheng: None. B. Wang: None. D.J. Lefer: None.
- © 2016 by American Heart Association, Inc.