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1 University of North Carolina
* To whom correspondence should be addressed. E-mail: zxu{at}aims.unc.edu.
The purpose of this study was to determine if exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase 3
(GSK-3). Treatment of cardiac H9c2 cells with ZnCl2 (10 µM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3 phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3 in H9c2 cells. The effect of zinc on GSK-3 activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the mTOR inhibitor rapamycin or the PKC inhibitor chelerythrine, implying that PI3K but not mTOR or PKC accounts for the action of zinc. In support of this interpretation, zinc induced a significant increase in Akt but not mTOR phosphorylation. Further experiments found that zinc also increased mitochondrial GSK-3 phosphorylation. This may indicate an involvement of mitochondria in zinc's action. The effect of zinc on mitochondrial GSK-3 phosphorylation was not altered by the mitochondrial KATP channel (mitoKATP) blocker 5-hydroxydecanoic acid (5-HD). Zinc applied at reperfusion reduced cell death in cells subjected to ischemia/reperfusion, indicating that zinc can prevent reperfusion injury. However, zinc was not able to exert protection in cells transfected with the constitutively active GSK-3 (GSK-3-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3. Cells transfected with the catalytically inactive GSK-3 (GSK-3-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3 inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through inhibition of GSK-3. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through inactivation of GSK-3. The PI3K/Akt signaling pathway is responsible for inactivation of GSK-3 by zinc.
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