Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart |
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Authors: | Táňa Ravingerová Jana Matejíková Jan Necká? Eva Andelová Franti?ek Kolá? |
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Institution: | (1) Institute for Heart Research, Slovak Academy of Sciences, Dubravská cesta 9, POB 104, Bratislava, 840 05, Slovak Republic;(2) Department of Developmental Cardiology, Institute of Physiology, Academy of Sciences of the Czech Republic and Centre for Cardiovascular Research, Prague, Czech Republic |
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Abstract: | 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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Keywords: | chronic hypoxia ischemic preconditioning myocardial infarction ventricular arrhythmias PI3K/Akt rat heart |
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