title: 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.affiliation: Istituto di Ricerche Biomediche A. Marxer, LCG-RBM/Serono Discovery, I-10010 Colleretto Giacosa, Italy. chiara.ferrandi@serono.com
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.forename: Rossana
authors.initials: R
authors.lastname: Ballerio
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaillard
authors.forename: Claudio
authors.initials: C
authors.lastname: Giachetti
authors.forename: Sonia
authors.initials: S
authors.lastname: Carboni
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Vitte
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gotteland
authors.forename: Rocco
authors.initials: R
authors.lastname: Cirillo
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003327:Coronary Disease / Q000503:physiopathology; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C489138:1,3-benzothiazol-2-yl(2-((2-(3-pyridinyl)ethyl)amino)-4-pyrimidinyl)acetonitrile; D000097:Acetonitriles; D052160:Benzothiazoles; D013844:Thiazoles; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases