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

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 muM) 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.

Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice

“…However, in chronic cardiac ischemia it is known that Akt is not regulated, and this has also been shown in our study (51). We found it to be of interest as well that TLR4 deficiency was associated with an activation of cardiac Akt.…”

Influence of ischemia/reperfusion and modulation of PI3K/Akt kinase pathway on matrix metalloproteinase-2 in rat hearts

“…Similarly to our finding, also other study documented increased phosphorylation of Akt kinase during acute IP (Tong et al 2000). Moreover, PI3K/Akt kinase pathway has been implicated in the mechanisms of various forms of cardioprotection (short-term and long-term), such as classical ischemic or hypoxic preconditioning and its delayed (second window) phase, as well as pharmacologically induced preconditioning Uchiyama et al 2004;Ravingerová et al 2007). The present study documented that application of wortmannin, inhibitor of PI3K/Akt kinase pathway, abolished the IP-induced changes in modulation of both Akt kinase and MMP-2 activities in rat hearts.…”

The role of PPAR in myocardial response to ischemia in normal and diseased heart

“…Cascades of ERK1/2 and PI3K and its effector protein kinase B (Akt) are implicated in protective mechanisms of ischemic preconditioning and other forms of intrinsic cardioprotection Ravingerová et al 2007). It has also been hypothesized that PPAR activation prior to I/R could confer preconditioning-like protection to the myocardium (Wynne et al 2005).…”