This Article Full Text Full Text (PDF) All Versions of this Article: 117/21/2761    most recent CIRCULATIONAHA.107.755066v1 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 PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Gomez, L. Articles by Ovize, M. PubMed PubMed Citation Articles by Gomez, L. Articles by Ovize, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy Hazardous Substances DB CYCLOSPORIN A Related Collections Cardiovascular Pharmacology Apoptosis Cell signalling/signal transduction Ischemic biology - basic studies Acute myocardial infarction Related Article

(Circulation. 2008;117:2761-2768.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Inhibition of GSK3β by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion

Ludovic Gomez, PhD; Mélanie Paillard, Bsc; Hélène Thibault, MD; Geneviève Derumeaux, MD, PhD; Michel Ovize, MD, PhD

From INSERM U886, Université Claude Bernard Lyon (L.G., M.P., H.T., G.D., M.O.), and Hôpital Louis Pradel, Hospices Civils de Lyon (H.T., G.D., M.O.), Lyon, France.

Correspondence to Professor Michel Ovize, INSERM U886, "Cardioprotection," Laboratoire de Physiologie Lyon-Nord, 8, Avenue Rockefeller, 69373 Lyon, France. E-mail ovize{at}sante.univ-lyon1.fr

Received November 26, 2007; accepted March 20, 2008.

Background— Opening of the mitochondrial permeability transition pore (mPTP) is a crucial event in lethal reperfusion injury. Phosphorylation (inhibition) of glycogen synthase kinase-3β (GSK3β) has been involved in cardioprotection. We investigated whether phosphorylated GSK3β may protect the heart via the inhibition of mPTP opening during postconditioning.

Methods and Results— Wild-type and transgenic GSK3β-S9A mice (the cardiac GSK3β activity of which cannot be inactivated) underwent 60 minutes of ischemia and 24 hours of reperfusion. At reperfusion, wild-type and GSK3β-S9A mice received no intervention (control), postconditioning (3 cycles of 1 minute ischemia and 1 minute of reperfusion), the mPTP inhibitor cyclosporine A (CsA; 10 mg/kg IV), or the GSK3β inhibitor SB216763 (SB21; 70 µg/kg IV). Infarct size was assessed by triphenyltetrazolium chloride staining. The resistance of the mPTP to opening after Ca²⁺ loading was assessed by spectrofluorometry on mitochondria isolated from the area at risk. In wild-type mice, infarct size was significantly reduced by postconditioning, CsA, and SB21, averaging 39±2%, 35±5%, and 37±4%, respectively, versus 58±5% of the area at risk in control mice (P<0.05). In GSK3β-S9A mice, only CsA, but not postconditioning or SB21, reduced infarct size. Postconditioning, CsA, and SB21 all improved the resistance of the mPTP in wild-type mice, but only CsA did so in GSK3β-S9A mice.

Conclusion— These results suggest that S9-phosphorylation of GSK3β is required for postconditioning and likely acts by inhibiting the opening of the mitochondrial permeability transition pore.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 2719-2720. [Full Text]