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An apoptosis signal-regulating kinase 1 inhibitor reduces cardiomyocyte apoptosis and infarct size in a rat ischemia-reperfusion model.

Authors: Gerczuk, PZ  Breckenridge, DG  Liles, JT  Budas, GR  Shryock, JC  Belardinelli, L  Kloner, RA  Dai, W 
Citation: Gerczuk PZ, etal., J Cardiovasc Pharmacol. 2012 Sep;60(3):276-82. doi: 10.1097/FJC.0b013e31825ea0fa.
Pubmed: (View Article at PubMed) PMID:22635076
DOI: Full-text: DOI:10.1097/FJC.0b013e31825ea0fa

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.

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CRRD Object Information
CRRD ID: 10412335
Created: 2015-11-17
Species: All species
Last Modified: 2015-11-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.