Document Detail

Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3beta.
MedLine Citation:
PMID:  18660440     Owner:  NLM     Status:  MEDLINE    
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-3beta (GSK-3beta). The treatment of cardiac H9c2 cells with ZnCl2 (10 microM) in the presence of zinc ionophore pyrithione for 20 min significantly enhanced GSK-3beta phosphorylation at Ser9, indicating that exogenous zinc can inactivate GSK-3beta in H9c2 cells. The effect of zinc on GSK-3beta 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-3beta phosphorylation. This may indicate an involvement of the mitochondria in the action of zinc. The effect of zinc on mitochondrial GSK-3beta 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-3beta (GSK-3beta-S9A-HA) mutant, suggesting that zinc prevents reperfusion injury by inactivating GSK-3beta. Cells transfected with the catalytically inactive GSK-3beta (GSK-3beta-KM-HA) also revealed a significant decrease in cell death, strongly supporting the essential role of GSK-3beta inactivation in cardioprotection. Moreover, zinc prevented oxidant-induced mPTP opening through the inhibition of GSK-3beta. Taken together, these data suggest that zinc prevents reperfusion injury by modulating the mPTP opening through the inactivation of GSK-3beta. The PI3K/Akt signaling pathway is responsible for the inactivation of GSK-3beta by zinc.
Guillaume Chanoit; SungRyul Lee; Jinkun Xi; Min Zhu; Rachel A McIntosh; Robert A Mueller; Edward A Norfleet; Zhelong Xu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-07-25
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  295     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2008 Sep 
Date Detail:
Created Date:  2008-09-08     Completed Date:  2008-10-16     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1227-H1233     Citation Subset:  IM    
Department of Anesthesiology, CB #7010, The Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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MeSH Terms
Blotting, Western
Cardiotonic Agents*
Cell Line
Cell Survival / drug effects
Cytosol / drug effects,  metabolism
DNA / biosynthesis,  genetics
Enzyme Inhibitors*
Glycogen Synthase Kinase 3 / antagonists & inhibitors*
Microscopy, Confocal
Mitochondria, Heart / drug effects*
Myocardial Reperfusion Injury / prevention & control*
Myocytes, Cardiac / drug effects*
Permeability / drug effects
Plasmids / genetics
Signal Transduction / drug effects
Zinc / pharmacology*
Grant Support
Reg. No./Substance:
0/Cardiotonic Agents; 0/Enzyme Inhibitors; 7440-66-6/Zinc; 9007-49-2/DNA; EC Synthase Kinase 3
Comment In:
Am J Physiol Heart Circ Physiol. 2009 Jan;296(1):H233-4; author reply H235   [PMID:  19116335 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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