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is a primary mechanism of cardiomyocyte protection by erythropoietin against oxidant-induced apoptosis
1 Sapporo Medical University School of Medicine
2 Sapporo Medical University
* To whom correspondence should be addressed. E-mail: miura{at}sapmed.ac.jp.
The aim of this study was to determine the role of glycogen synthase kinase-3
(GSK-3) in cardiomyocyte protection afforded by erythropoietin (EPO) against oxidant stress-induced apoptosis. Treatment with EPO (10 units/ml) induced Ser473-phosphorylation of Akt and Ser9-phosphorylation of GSK-3 and significantly reduced the proportion of apoptotic H9c2 cardiomyocytes after exposure to H2O2 from 38.3±2.7% to 26.0±2.9%. This protection was not detected in cells transfected with constitutively active GSK-3 (S9A), which lacks Ser9 for inhibitory phosphorylation. The anti-apoptotic effect of EPO was mimicked completely by GSK-3 knock-down using siRNA and partly by transfection with kinase deficient GSK-3 (K85R). The level of co-localization of intracellular GSK-3 with mitochondria assessed by EGFP-tagged GSK-3 or immunocytochemistry was not altered by EPO treatment. However, EPO increased the level of Ser9-phospho-GSK-3 co-localized with mitochondria by 50% in a phosphatidylinositol-3-kinase-dependent manner. Mitochondrial translocation of BAX after exposure to H2O2 was inhibited by EPO pretreatment and by GSK-3 knock-down. These results suggest that suppression of GSK-3 activity by Akt-mediated Ser9-phosphorylation in the mitochondria affords cardiomyocytes tolerance against oxidant-induced apoptosis, possibly by inhibiting access of BAX to the mitochondria.
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