Abstract 1599: Hydrogen Sulfide Mediates Myocardial Preconditioning via Upregulation of Antioxidant and Anti-Apoptotic Signaling Pathways
The emergence of hydrogen sulfide (H2S) as a potent cardioprotective mediator necessitates the elucidation of its cytoprotective mechanisms. Therefore, we evaluated potential mechanisms of H2S-mediated cardioprotection using an in vivo model of preconditioning (PC). The H2S donor, IK1001 (100 μg/kg), or vehicle was administered to mice via an intravenous injection 24 hours prior to left coronary artery occlusion and reperfusion. Mice were subjected to 45 min of myocardial ischemia followed by reperfusion for up to 24 hr, during which time the extent of myocardial infarction was evaluated, serum troponin-I levels were measured, and the degree of oxidative stress was assessed. In separate studies, mice were treated with IK1001 and myocardial tissue was collected during both the early (30 min and 2hr) and late (24 hr) PC periods to evaluate potential cellular targets of H2S. IK1001 provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, serum troponin-I levels, and oxidative stress. Additional studies revealed that during the early PC period H2S increased the nuclear localization of Nrf-2, a transcription factor that regulates the gene expression of a number of antioxidants, and increased the nuclear localization of phosphorylated STAT-3. During the late PC period, H2S increased the expression of the antioxidants, Trx-1 and Trx-2, increased the expression of HSP90, HSP70, Bcl-2, and Bcl-xL and also inactivated the pro-apoptogen Bad. Our results reveal that the cardioprotective effects of H2S are mediated in large part by a combination of antioxidant and anti-apoptotic signaling.