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Alcohol and Alcoholism Advance Access originally published online on November 25, 2008
Alcohol and Alcoholism 2009 44(1):20-24; doi:10.1093/alcalc/agn098
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© The Author 2008. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved

Ethanol Prevents Oxidant-Induced Mitochondrial Permeability Transition Pore Opening in Cardiac Cells

Kunyan Zhou1,{dagger}, Lei Zhang1,{dagger}, Jinkun Xi1,2{dagger}, Wei Tian1 and Zhelong Xu2,*

1 Heart Institute, North China Coal Medical University, Tangshan, Hebei 063000, China and
2 Department of Anesthesiology, University of North Carolina, Chapel Hill, NC 27599, USA

* Corresponding author: Department of Anesthesiology, University of North Carolina, Chapel Hill, NC 27599, USA. Tel: +1-919-843-4174; Fax: +1-919-843-3805; E-mail: zxu{at}aims.unc.edu

Received 5 August 2008; first review notified 9 September 2008; in revised form 23 September 2008; accepted 16 October 2008; advance access publication 25 November 2008


  Abstract

Aims: The purpose of this study was to determine if ethanol prevents the mitochondrial permeability transition pore (mPTP) opening via glycogen synthase kinase 3β (GSK-3β). Methods: Cardiac H9c2 cells were exposed to ethanol (10–1000 µM) for 20 min. GSK-3β activity was determined by measuring its phosphorylation at Ser9. Mitochondrial membrane potential ({Delta}{Psi}m) was assessed by imaging (confocal microscopy) H9c2 cells loaded with tetramethylrhodamine ethyl ester (TMRE). To activate GSK-3β, cells were transfected with constitutively active GSK-3β (GSK-3β-S9A-HA) mutant plasmid. Results: Treatment of cardiac cells with low doses of ethanol (10–500 µM) significantly enhanced GSK-3β phosphorylation, indicating that ethanol can inactivate GSK-3β in H9c2 cells. The effect of ethanol on GSK-3β activity was reversed by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and ethanol could enhance Akt phosphorylation, implying that the PI3K/Akt pathway accounts for the action of ethanol. Ethanol prevented oxidant (H2O2)-induced loss {Delta}{Psi}m, an effect that was reversed by LY294002, indicating that ethanol can modulate the mPTP opening caused by oxidant stress through the PI3K/Akt pathway. Ethanol failed to preserve {Delta}{Psi}m in cells transfected with the constitutively active GSK-3β (GSK-3β-S9A-HA) mutant, suggesting that ethanol prevents the mPTP opening by inactivating GSK-3β. Conclusions: These data suggest that ethanol prevents the mPTP opening through inactivation of GSK-3β. The PI3K/Akt signaling pathway is responsible for inactivation of GSK-3β by ethanol.

{dagger} Contributed equally to this work.


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