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

被引:134
作者
Ferrandi, C
Ballerio, R
Gaillard, P
Giachetti, C
Carboni, S
Vitte, PA
Gotteland, JP
Cirillo, R
机构
[1] LCG RBM Serono Discovery, Expt Pharmacol Unit, Ist Ric Biomed A Marxer, I-10010 Colleretto, Giacosa, Italy
[2] Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
关键词
myocardial ischemia/reperfusion; JNK; apoptosis; JNK inhibitor;
D O I
10.1038/sj.bjp.0705873
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 It. 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 mug 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 hemodinamics 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.
引用
收藏
页码:953 / 960
页数:8
相关论文
共 23 条
[1]   Oxidative stress activates extracellular signal-regulated kinases through Src and ras in cultured cardiac myocytes of neonatal rats [J].
Aikawa, R ;
Komuro, I ;
Yamazaki, T ;
Zou, YZ ;
Kudoh, S ;
Tanaka, M ;
Shiojima, I ;
Hiroi, Y ;
Yazaki, Y .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (07) :1813-1821
[2]   Direct activation of mitochondrial apoptosis machinery by c-Jun N-terminal kinase in adult cardiac myocytes [J].
Aoki, H ;
Kang, PM ;
Hampe, J ;
Yoshimura, K ;
Noma, T ;
Matsuzaki, M ;
Izumo, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (12) :10244-10250
[3]   Protein kinase activation and myocardial ischemia/reperfusion injury [J].
Armstrong, SC .
CARDIOVASCULAR RESEARCH, 2004, 61 (03) :427-436
[4]   A CRITICAL-LOOK AT CURRENTLY USED INDIRECT INDEXES OF MYOCARDIAL OXYGEN-CONSUMPTION [J].
BALLER, D ;
BRETSCHNEIDER, HJ ;
HELLIGE, G .
BASIC RESEARCH IN CARDIOLOGY, 1981, 76 (02) :163-181
[5]  
BARLING B, 1998, BASIC RES CARDIOL, V93, P71
[6]   Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart - p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion [J].
Bogoyevitch, MA ;
GillespieBrown, J ;
Ketterman, AJ ;
Fuller, SJ ;
BenLevy, R ;
Ashworth, A ;
Marshall, CJ ;
Sugden, PH .
CIRCULATION RESEARCH, 1996, 79 (02) :162-173
[7]   Stress- and cell type-dependent regulation of transfected c-Jun N-terminal kinase and mitogen-activated protein kinase kinase isoforms [J].
Butterfield, L ;
Zentrich, E ;
Beekman, A ;
Heasley, LE .
BIOCHEMICAL JOURNAL, 1999, 338 :681-686
[8]  
CARBONI S, 2004, J PHARM EXP THER, V310
[9]   Poly(ADP-ribose) polymerase: killer or conspirator? The 'suicide hypothesist' revisited [J].
Chiarugi, A .
TRENDS IN PHARMACOLOGICAL SCIENCES, 2002, 23 (03) :122-129
[10]   Stimulation of "Stress-regulated" mitogen-activated protein kinases (stress-activated protein kinases c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses [J].
Clerk, A ;
Fuller, SJ ;
Michael, A ;
Sugden, PH .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (13) :7228-7234