HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/H1227    most recent 00610.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Chanoit, G. Articles by Xu, Z. PubMed PubMed Citation Articles by Chanoit, G. Articles by Xu, Z.

Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3β

Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Submitted 11 June 2008 ; accepted in final form 21 July 2008

The purpose of this study was to determine whether exogenous zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via glycogen synthase kinase-3β (GSK-3β). The treatment of cardiac H9c2 cells with ZnCl₂ (10 µM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3β phosphorylation at Ser⁹, indicating that exogenous zinc can inactivate GSK-3β in H9c2 cells. The effect of zinc on GSK-3β activity was blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 but not by the mammalian target of rapamycin (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-3β phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3β phosphorylation was not altered by the mitochondrial ATP-sensitive K⁺ channel blocker 5-hydroxydecanoic acid. Zinc applied at reperfusion reduced cell death in cells subjected to simulated 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-3β (GSK-3β-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3β. Cells transfected with the catalytically inactive GSK-3β (GSK-3β-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3β inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3β. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3β. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3β by zinc.

h9c2 cell; oxidant stress; simulated ischemia

This article has been cited by other articles:

				M. M. Mocanu and D. M. Yellon Letter to the editor: "Zinc and cardioprotection: the missing link" Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H233 - H234. [Full Text] [PDF]

				G. Chanoit, S. Lee, and Z. Xu Reply to "Letter to the editor: 'Zinc and cardioprotection: the missing link'" Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H235 - H235. [Full Text] [PDF]

				P. Zhai and J. Sadoshima Overcoming an Energy Crisis?: An Adaptive Role of Glycogen Synthase Kinase-3 Inhibition in Ischemia/Reperfusion Circ. Res., October 24, 2008; 103(9): 910 - 913. [Full Text] [PDF]