Effect of Pressure Overload on Cardioprotection via PI3K-Akt: Comparison of Postconditioning, Insulin, and Pressure Unloading

Abstract

Pressure overload reduces PI3K-Akt signaling following IR. However, a differential in PI3K-Akt signaling was not observed in ischemia-reperfused, insulin-treated, and postconditioned hearts, suggesting involvement of pathways other than PI3K-Akt for the effect of pressure on IS. Importantly, pressure unloading at reperfusion represents a novel and effective cardioprotective maneuver.

Pressure Overload Regulates Expression of Cytokines, γH2AX, and Growth Arrest- and DNA-Damage Inducible Protein 153 via Glycogen Synthase Kinase-3β in Ischemic-Reperfused Hearts

“…Pressure overload causes significant reduction in myocardial level of phospho-GSK-3β in the ischemic-reperfused heart and inhibition of GSK-3β, with either LiCl or SB216763, causes significant reduction in infarct size with the effect more marked for pressure overloaded hearts, thereby abrogating pressure-related differential in infarct size. 18,19 In the present study, we used flow cytometry for assessment of both ψ m and delineation of cell death via apoptosis and necrosis because this approach offers the advantage of examining these parameters using the same pool of cardiac cells; ψ m is used as a surrogate marker for assessment of MPT pore because its induction is associated with loss of ψ m and associated cell death. 24,25 Pressure overload was associated with markedly reduced ratio of JC-1 aggregates to monomers suggestive of greater collapse of ψ m .…”

“…It is increasingly apparent that GSK-3β is a converging point for multiple signaling pathways that regulate the MPT pore in the ischemic-reperfused heart, thereby determining cell fate. [9][10][11]18,19 Accordingly, inhibition of GSK-3β, via phosphorylation at serine 9 residue or with pharmacological inhibitors, exerts cardioprotection. Pressure overload causes significant reduction in myocardial level of phospho-GSK-3β in the ischemic-reperfused heart and inhibition of GSK-3β, with either LiCl or SB216763, causes significant reduction in infarct size with the effect more marked for pressure overloaded hearts, thereby abrogating pressure-related differential in infarct size.…”

“…[16][17][18][19][20][22][23][24][25][26] Briefly, hearts of male Sprague-Dawley rats were subjected to global ischemia (40 minutes)-reperfusion (15 minutes) with buffer lacking or containing 1 mmol/L of LiCl; the perfusion pressure was set at either 80 or 160 of cmH 2 O. Time-controlled normoxic hearts served as controls. Thereafter, cardiac cell preparations were subjected to flow cytometry analysis and immunofluorescent assays.…”

“…16,17 Furthermore, pressure overload is associated with reduction in myocardial level of phosphorylated GSK-3β (ie, the inactive form) and inhibition of GSK-3β causes significant reduction in infarct size with the effect being more marked for pressure overloaded hearts. 18,19 Thus, in the present study, we tested the hypothesis that the exacerbating impact of pressure overload in the isolated ischemic-reperfused heart relates to GSK-3β-dependent increased DNA injury, GADD153 expression and upregulation of endogenous inflammatory response, and greater cell death. Accordingly, using lithium chloride (LiCl), we explored the impact of inhibition of GSK-3β on myocardial generation of anti-and proinflammatory cytokines (ie, interleukins [ILs] 10, 17, and 23), γH2AX (a sensitive marker of double strand DNA breaks), GADD153 expression, mitochondrial membrane potential, and cell death in ischemic-reperfused hearts subjected to low and high perfusion pressures.…”

A labdane diterpene exerts ex vivo and in vivo cardioprotection against post-ischemic injury: Involvement of AKT-dependent mechanisms

“…A large number of studies have shown that the survival kinases PI3K/AKT play a critical role in the protection afforded by postconditioning in healthy myocardium [39,40]. AKT has been reported as a cardioprotective enzyme that inhibits apoptosis and preserves cardiac function in clinically relevant cardiac disease models [41].…”