Abstract 16646: The Novel Hydrogen Sulfide Donor Diallyl Trisulfide Protects Against Ischemia-Reperfusion Injury by Inhibition of Mitochondrial Respiration

Abstract

Hydrogen sulfide (H2S) is enzymatically produced in the body, and has a range of cardioprotective effects including: anti-inflammatory, antioxidant, and anti-apoptotic actions, and inhibition of mitochondrial respiration. However, because of its volatile and reactive nature, H2S remains a challenge to administer therapeutically. In this study we investigate the novel, stable H2S donor diallyl trisulfide (DATS) in an in vivo murine model of myocardial ischemia-reperfusion (MI/R) injury, as well as on mitochondrial respiration in isolated murine mitochondria. Mice (C57BL6/J, 8-10 wk old) were subjected to 45 minutes of myocardial ischemia followed by reperfusion for 24 hr. DATS or vehicle was administered just prior to reperfusion. At 24 hr of reperfusion, infarction per area-at-risk (INF/AAR) was evaluated with Evan's Blue dye and 2,3,5-tetrazolium chloride staining and serum was collected for Troponin-I measurement with a commercial kit. Cardiac mitochondria were isolated from a separate group of mice and State 3 respiration was determined in the presence or absence of DATS. H2S release from DATS was determined using a polarographic H2S electrode. DATS (200 µg/kg) reduced the INF/AAR by 61% (p<0.001 vs. Vehicle). DATS also reduced circulating troponin-I levels from 43.58±5.7 ng/mL to 16.38±5.0 ng/mL (p=0.003 vs. Vehicle). Application of DATS to isolated mitochondria resulted in a release of H2S at a rate of 0.91+/-0.19 pmol/min. Mitochondrial State 3 respiration significantly decreased 70% by the addition of 200 µM DATS (p<0.001 vs. Control). Taken together, these data demonstrate that DATS is an effective H2S donor, which significantly reduces infarct size following MI/R injury, potentially by inhibition of mitochondrial respiration.