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Cardiac protection by mitoK_ATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning

¹Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and ²Department of Pharmacology, Düzce College of Medicine, Abant Ìzzet Baysal University, Düzce, Turkey

Submitted 13 July 2005 ; accepted in final form 11 January 2006

This investigation elucidates the Akt/mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channel signaling pathway in late pharmacological preconditioning, using the mitoK_ATP channel openers BMS-191095 (BMS) and diazoxide (DE). BMS (1 mg/kg ip) and DE (7 mg/kg ip) alone or BMS plus wortmannin (WTN, 15 µg/kg ip), an inhibitor of phosphatidylinositol 3-kinase, and BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoK_ATP channels, were administered to male mice. Twenty-four hours later, hearts were isolated and subjected to 40 min of ischemia and 120 min of reperfusion via Langendorff's apparatus. Both BMS and DE reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced LDH release. Coadministration of BMS and WTN abolished the beneficial effects of BMS on cardiac function. Moreover, BMS and DE accelerated Akt phosphorylation in cardiac tissue as determined by Western blot analysis and also significantly reduced apoptosis compared with ischemic control. WTN significantly suppressed BMS-induced Akt phosphorylation, whereas 5-HD had no effect on Akt phosphorylation in cytosol, and the effect of BMS on apoptosis was abolished. It is concluded that the cardioprotective effect by mitoK_ATP channels is attributed to the translocation of phosphorylated Akt from cytosol to mitochondria.

BMS-191095; diazoxide; apoptosis; mitochondrial ATP-sensitive K channels

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