An Apoptosis Signal-regulating Kinase 1 Inhibitor Reduces Cardiomyocyte Apoptosis and Infarct Size in a Rat Ischemia-reperfusion Model

Purposes: We determined whether a small molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1-i) could reduce myocardial infarct size in a rat ischemia/reperfusion model. Methods and Results: Sprague-Dawley rats were randomized to 3 groups: ASK1-i infusion (n = 16), vehicle infusion (n = 16), or ischemic preconditioning (IPC; n = 15). Infusion of ASK1-i (10 mg/kg, iv) or vehicle commenced 45 minutes before myocardial ischemia. IPC consisted of 3 cycles of 3 minutes of coronary occlusion followed by 5 minutes of reperfusion immediately before index myocardial ischemia, which consisted of 30-minute left coronary occlusion followed by 180 minutes of reperfusion. Pathologic analysis revealed no significant difference in the ischemic risk size among the 3 groups. ASK1-I and IPC significantly reduced myocardial infarct size (27.7% +/- 3.3%, 16.5% +/- 3.4%, and 41.5% +/- 4.8% in the ASK1-i group, the IPC group, and the vehicle group, respectively; P = 0.0002) and apoptosis (the percentage of apoptotic nuclei averaged 11.6% +/- 1.0%, 10.2% +/- 1.7%, and 17.7% +/- 2.0% in the ASK1-i group, IPC group, and vehicle group, respectively, P = 0.0055). Conclusions: A small molecule inhibitor of ASK1 was shown for the first time to reduce apoptosis and myocardial infarct size in a rat model of ischemia/reperfusion.