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

Abstract

1 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. 2 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 microg 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. 3 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 hemodynamics or reducing ST-segment displacement. 4 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. 5 These results demonstrate that blocking the JNK pathway may represent a novel therapeutic approach for treating myocardial ischemia/reperfusion-induced cardiomyocyte death.

• Authors: Chiara Ferrandi, Rossana Ballerio, Pascale Gaillard, Claudio Giachetti, Sonia Carboni, Pierre-Alain Vitte, Jean-Pierre Gotteland, Rocco Cirillo
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 142 Issue 6 Pg. 953-60 (Jul 2004) ISSN: 0007-1188 [Print] England
• PMID: 15210584 (Publication Type: Journal Article)

Chemical References

• 1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile
• Acetonitriles
• Benzothiazoles
• Thiazoles
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Acetonitriles (pharmacology)
• Anesthesia
• Animals
• Apoptosis (drug effects)
• Benzothiazoles
• Blood Pressure (drug effects)
• Blotting, Western
• Coronary Disease (physiopathology)
• DNA Fragmentation (drug effects)
• Enzyme Activation (drug effects)
• Heart Rate (drug effects)
• Hemodynamics (drug effects)
• Immunohistochemistry
• In Situ Nick-End Labeling
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Male
• Myocardial Infarction (etiology, pathology, prevention & control)
• Myocardial Reperfusion Injury (complications, physiopathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Phosphorylation (drug effects)
• Rats
• Rats, Sprague-Dawley
• Thiazoles (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)