Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart

被引:9
作者
Táňa Ravingerová
Jana Matejíková
Jan Neckář
Eva Andelová
František Kolář
机构
[1] Slovak Academy of Sciences,Institute for Heart Research
[2] Institute of Physiology,Department of Developmental Cardiology
[3] Academy of Sciences of the Czech Republic and Centre for Cardiovascular Research,undefined
来源
Molecular and Cellular Biochemistry | 2007年 / 297卷
关键词
chronic hypoxia; ischemic preconditioning; myocardial infarction; ventricular arrhythmias; PI3K/Akt; rat heart;
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学科分类号
摘要
Endogenous cardiac protection against prolonged ischemic insult can be achieved by repeated brief episodes of ischemia (hypoxia) or by cardiac adaptation to various stresses such as chronic hypoxia. Activation of phosphatidylinositol 3-kinase (PI3K)/Akt is involved in antiapoptotic effects, however, it is not clear whether it is required for overall heart salvage including protection against myocardial infarction and arrhythmias. We focussed on the potential common role of PI3K/Akt in anti-infarct protection, in the experimental settings of long-term adaptation to chronic intermittent hypobaric hypoxia (IHH; 8 h/day, 25–30 exposures, in vivo rats) and acute ischemic preconditioning (IP; Langendorff-perfused hearts). In addition, we explored the role of PI3K/Akt in susceptibility to ischemic ventricular arrhythmias. In normoxic open-chest rats, PI3K/Akt inhibitor LY294002 (LY; 0.3 mg/kg) given 5 min before test occlusion/reperfusion (I/R) did not affect infarct size (IS) normalized to the size of area at risk (AR). In hypoxic rats, LY partially attenuated IS-limiting effect of IHH (IS/AR 59.7 ± 4.1% vs. 51.8 ± 4.4% in the non-treated rats; p > 0.05) and increased IS/AR to its value in normoxic rats (64.9 ± 5.1%). In the isolated hearts, LY (5 μM) applied 15 min prior to I/R completely abolished anti-infarct protection by IP (IS/AR 55.0 ± 4.9% vs. 15.2 ± 1.2% in the non-treated hearts and 42.0 ± 5.5% in the non-preconditioned controls; p < 0.05). In the non-preconditioned hearts, PI3K/Akt inhibition did not modify IS/AR, on the other hand, it markedly suppressed arrhythmias. In the LY-treated isolated hearts, the total number of ventricular premature beats and the incidence of ventricular tachycardia (VT) was reduced from 518 ± 71 and 100% in the controls to 155 ± 15 and 12.5%, respectively (p < 0.05). Moreover, bracketing of IP with LY did not reverse antiarrhythmic effect of IP. These results suggest that activation of PI3K/Akt cascade plays a role in the IS-limiting mechanism in the rat heart, however, it is not involved in the mechanisms of antiarrhythmic protection.
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页码:111 / 120
页数:9
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共 292 条
[41]  
Dietz R(1996)Protein kinase cascades in the regulation of cardiac hypertrophy J Mol Cell Cardiol 28 2129-2138
[42]  
Bergmann MW(2005)Preconditioning-induced cardioprotection and release of the second messenger inositol (1,4,5)-trisphosphate are both abolished by neomycin in rabbit heart Cardiovasc Drugs Ther 19 33-40
[43]  
Kolar F(2005)Ins(1,4,5)P Circulation 112 1701-1710
[44]  
Ostadal B(2001) during myocardial ischemia and its relationship to the development of arrhythmias Circ Res 88 1020-1027
[45]  
Neckar J(2005)Erythropoietin just before reperfusion reduces both lethal arrhythmias and infarct size via the phosphatidylinositol-3 kinase-dependent pathway in canine hearts J Pharmacol Exp Ther 315 1125-35
[46]  
Ostadal B(2001)Nontranscriptional regulation of cardiac repolarization currents by testosterone Circ Res 89 437-444
[47]  
Kolar F(2004)Myocardial Akt activation and gender: increased nuclear activity in females versus males Fundam Clin Pharmacol 18 139-151
[48]  
Pelouch V(1993)Gender differences in cardioprotection against ischemia-reperfusion injury in adult rat hearts: focus on Akt and PKC signaling J Mol Cell Cardiol 25 1427-1438
[49]  
Kolar F(1999)Gender-based differences in cardiac repolarization in mouse ventricle Am J Physiol 277 H999-H1006
[50]  
Ostadal B(2001)Sex differences in ventricular repolarization: from cardiac electrophysiology to Torsades de Pointes Circ Res 89 641-644