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

Abstract

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.

• Authors: Paul Z Gerczuk, David G Breckenridge, John T Liles, Grant R Budas, John C Shryock, Luiz Belardinelli, Robert A Kloner, Wangde Dai
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 60 Issue 3 Pg. 276-82 (Sep 2012) ISSN: 1533-4023 [Electronic] United States
• PMID: 22635076 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• MAP Kinase Kinase Kinase 5

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Disease Models, Animal
• MAP Kinase Kinase Kinase 5 (antagonists & inhibitors, metabolism)
• Male
• Myocardial Infarction (drug therapy, enzymology, pathology)
• Myocardial Reperfusion Injury (drug therapy, enzymology, pathology)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley