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Title

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

Authors
Ferrandi, Chiara
Ballerio, Rossana
Gaillard, Pascale
Giachetti, Claudio
Vitte, Pierre-Alain
Gotteland, Jean-Pierre
Cirillo, Rocco
Published in British Journal of Pharmacology. 2004, vol. 142, no. 6, p. 953-960
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.
Keywords Acetonitriles/pharmacologyAnesthesiaAnimalsApoptosis/drug effectsBenzothiazolesBlood Pressure/drug effectsBlotting, WesternCoronary Disease/physiopathologyDNA Fragmentation/drug effectsEnzyme Activation/drug effectsHeart Rate/drug effectsHemodynamics/drug effectsImmunohistochemistryIn Situ Nick-End LabelingJNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolismMaleMyocardial Infarction/etiology/pathology/prevention & controlMyocardial Reperfusion Injury/complications/physiopathology/prevention & controlMyocytes, Cardiac/drug effects/metabolism/pathologyPhosphorylation/drug effectsRatsRats, Sprague-DawleyThiazoles/pharmacologyp38 Mitogen-Activated Protein Kinases/metabolism
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PMID: 15210584
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FERRANDI, Chiara et al. Inhibition of c-Jun N-terminal kinase decreases cardiomyocyte apoptosis and infarct size after myocardial ischemia and reperfusion in anaesthetized rats. In: British Journal of Pharmacology, 2004, vol. 142, n° 6, p. 953-960. https://archive-ouverte.unige.ch/unige:89904

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Deposited on : 2016-12-06

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