Inhibition of c-Jun N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats

Authors


Experimental Pharmacology Unit, LCG-RBM/Serono Discovery, Via Ribes 1, I-10010 Colleretto Giacosa, Italy. E-mail: chiara.ferrandi@serono.com

Abstract

  • Myocardial ischemia/reperfusion is associated with inflammation, apoptosis and necrosis. During this process, c-jun N-terminal kinase is activated in cardiac myocytes resulting in apoptosis.

  • This study investigates the effects of AS601245, a nonpeptide ATP competitive JNK inhibitor, on infarct size caused by myocardial ischemia/reperfusion in anaesthetized rats. The left descending coronary artery of anaesthetized rats was occluded for 30 min and then reperfused for 3 h. AS601245 was administered 5 min before the end of the ischemia period as an i.v. bolus (1.5, 4.5 or 15 mg kg−1 i.v.) followed by continuous i.v. infusion (18, 55 and 183 μg kg−1 min−1, respectively) during reperfusion. Controls received saline only. 3-Aminobenzamide, a poly(ADP-ribose) polymerase inhibitor, was used as reference compound at 10 mg kg−1 i.v. bolus plus 0.17 mg kg−1 min−1 continuous infusion.

  • AS601245 significantly reduced infarct size at 4.5 mg kg−1 (−44%; P<0.001) and 15 mg kg−1 i.v. (−40.3%; P<0.001) similarly to 3-aminobenzamide (−44.2%; P<0.001). This protective effect was obtained without affecting hemodinamics or reducing ST-segment displacement.

  • The beneficial effects on infarct size correlated well with the reduction of c-jun phosphorylation (−85%; P<0.001 versus control) and of TUNEL-positive cells (−82.1%; P<0.001) in post-ischemic cardiomyocytes. No change in the phosphorylation state of p38 MAPK and ERK in post-ischemic heart was observed in the presence of AS601245 in comparison to the vehicle-treated group.

  • These results demonstrate that blocking the JNK pathway may represent a novel therapeutic approach for treating myocardial ischemia/reperfusion-induced cardiomyocyte death.

British Journal of Pharmacology (2004) 142, 953–960. doi:10.1038/sj.bjp.0705873

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