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1Second Department of Internal Medicine and 2Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan
Submitted 5 August 2005 ; accepted in final form 21 March 2006
The aim of this study was to determine whether erythropoietin (EPO) affords additional cardioprotection to the preconditioned myocardium by enhanced phosphorylation of Akt, STAT3, or glycogen synthase kinase-3
(GSK-3). Preconditioning (PC) with 5-min ischemia/5-min reperfusion and EPO (5,000 U/kg iv) reduced infarct size (as % of area at risk, %IS/AR) after 20-min ischemia in rat hearts in situ from 56.5 ± 1.8% to 25.2 ± 2.1% and to 36.2 ± 2.8%, respectively. PC-induced protection was significantly inhibited by a protein kinase C inhibitor, chelerythrine (5 mg/kg), and slightly blunted by a phosphatidylinositol-3-kinase inhibitor, wortmannin (15 µg/kg). The opposite pattern of inhibition was observed for EPO-induced protection. The combination of PC and EPO further reduced %IS/AR to 8.9 ± 1.9%, and this protection was inhibited by chelerythrine and wortmannin. The additive effects of PC and EPO on infarct size were mirrored by their effects on the level of phosphorylated GSK-3 at 5 min after reperfusion but not their effects on the level of phospho-Akt or phospho-STAT3. To mimic phosphorylation-induced inhibition of GSK-3 activity, SB-216763 (SB), a GSK-3 inhibitor, was administered before ischemia or 5 min before reperfusion. Infarct size was significantly reduced by preischemic injection (%IS/AR = 40.4 ± 2.2% by 0.6 mg/kg SB and 34.0 ± 1.8% by 1.2 mg/kg SB) and also by prereperfusion injection (%IS/AR = 32.0 ± 2.0% by 1.2 mg/kg SB). These results suggest that EPO and PC afford additive infarct size-limiting effects by additive phosphorylation of GSK-3 at the time of reperfusion by Akt-dependent and -independent mechanisms.
infarct size; phosphatidylinositol-3-kinase; protein kinase C; Akt
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