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1 Second Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
* To whom correspondence should be addressed. E-mail: miura{at}sapmed.ac.jp.
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, i.v.) 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 (PI3K) 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 chelerytheine 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, SB216763 (SB), a GSK-3 inhibitor, was administered before ischemia or 5 min before reperfusion. Infarct size was significantly reduced by pre-ischemic 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 pre-reperfusion 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.
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