alexa Effect of pressure overload on cardioprotection via PI3K-Akt: comparison of postconditioning, insulin, and pressure unloading.


Journal of Clinical & Experimental Cardiology

Author(s): Mozaffari MS, Liu JY, Schaffer SW

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Abstract BACKGROUND: Postconditioning (PC) and insulin exert cardioprotection by activating phosphatidylinositol-3 kinase (PI3K) signaling. Because pressure overload exacerbates ischemia-reperfusion (IR) injury, we tested the hypothesis that (i) pressure overload attenuates PC- and insulin-induced cardioprotection, an effect caused by reduced PI3K-Akt signaling and (ii) pressure unloading confers cardioprotection comparable to either PC or insulin. METHODS: Infarct size (IS) and levels of relevant proteins (i.e., Akt, glycogen synthase kinase-3beta (GSK-3beta), 3'-phosphoinositide dependent kinase 1 (PDK1), phosphatase and tensin homolog on chromosome ten (PTEN)) were determined in hearts subjected to IR. RESULTS: Pressure overload increased IS in association with changes in protein levels consistent with reduced PI3K-Akt signaling (i.e., ischemic reperfused vs. normoxic hearts). PC and insulin reduced IS but it was greater in hearts perfused at the higher, than the lower, pressure. Wortmannin (PI3K inhibitor) partially reversed PC-induced cardioprotection, with IS being greater in the high-pressure group. Pressure unloading during reperfusion caused the most marked reduction in IS whereas pressure loading abolished PC-induced cardioprotection. Nonetheless, the phospho-Akt/total Akt ratios and phospho-GSK-3beta levels were unaffected by perfusion pressure in insulin-treated or postconditioned hearts. Moreover, protein levels were similar in pressure-unloaded and pressure-loaded hearts. CONCLUSIONS: 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. This article was published in Am J Hypertens and referenced in Journal of Clinical & Experimental Cardiology

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