Published Online
on May 19, 2008

A more recent version of this article appeared on May 27, 2008

This Article 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 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gomez, L. Articles by Ovize, M. Search for Related Content 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

Submitted on November 26, 2007
Accepted on March 20, 2008

Inhibition of GSK3 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, and 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.

^* To whom correspondence should be addressed. E-mail: ovize{at}sante.univ-lyon1.fr.

Background—Opening of the mitochondrial permeability transition pore (mPTP) is a crucial event in lethal reperfusion injury. Phosphorylation (inhibition) of glycogen synthase kinase-3 (GSK3) has been involved in cardioprotection. We investigated whether phosphorylated GSK3 may protect the heart via the inhibition of mPTP opening during postconditioning.

Methods and Results—Wild-type and transgenic GSK3-S9A mice (the cardiac GSK3 activity of which cannot be inactivated) underwent 60 minutes of ischemia and 24 hours of reperfusion. At reperfusion, wild-type and GSK3-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 GSK3 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 GSK3-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 GSK3-S9A mice.

Conclusion—These results suggest that S9-phosphorylation of GSK3 is required for postconditioning and likely acts by inhibiting the opening of the mitochondrial permeability transition pore.

Key words: ischemia • myocardial infarction • reperfusion

Related Article:

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

This article has been cited by other articles:

				S. Tamareille, N. Ghaboura, F. Treguer, D. Khachman, A. Croue, D. Henrion, A. Furber, and F. Prunier Myocardial reperfusion injury management: erythropoietin compared with postconditioning Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2035 - H2043. [Abstract] [Full Text] [PDF]

				G. Heusch No RISK, no ... cardioprotection? A critical perspective Cardiovasc Res, November 1, 2009; 84(2): 173 - 175. [Full Text] [PDF]

				J. Musiolik, P. van Caster, A. Skyschally, K. Boengler, P. Gres, R. Schulz, and G. Heusch Reduction of infarct size by gentle reperfusion without activation of reperfusion injury salvage kinases in pigs Cardiovasc Res, August 25, 2009; (2009) cvp271v2. [Abstract] [Full Text] [PDF]

				P. Sicard, S. Jacquet, K. S. Kobayashi, R. A. Flavell, and M. S. Marber Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1 Cardiovasc Res, July 15, 2009; 83(2): 277 - 284. [Abstract] [Full Text] [PDF]

				L. Gomez, B. Li, N. Mewton, I. Sanchez, C. Piot, M. Elbaz, and M. Ovize Inhibition of mitochondrial permeability transition pore opening: translation to patients Cardiovasc Res, July 15, 2009; 83(2): 226 - 233. [Abstract] [Full Text] [PDF]

				M. Juhaszova, D. B. Zorov, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Role of Glycogen Synthase Kinase-3{beta} in Cardioprotection Circ. Res., June 5, 2009; 104(11): 1240 - 1252. [Abstract] [Full Text] [PDF]

				S. Miyamoto, M. Rubio, and M. A. Sussman Nuclear and mitochondrial signalling Akts in cardiomyocytes Cardiovasc Res, May 1, 2009; 82(2): 272 - 285. [Abstract] [Full Text] [PDF]

				A. Skyschally, P. van Caster, K. Boengler, P. Gres, J. Musiolik, D. Schilawa, R. Schulz, and G. Heusch Ischemic Postconditioning in Pigs: No Causal Role for RISK Activation Circ. Res., January 2, 2009; 104(1): 15 - 18. [Abstract] [Full Text] [PDF]

				K. Zhou, L. Zhang, J. Xi, W. Tian, and Z. Xu Ethanol Prevents Oxidant-Induced Mitochondrial Permeability Transition Pore Opening in Cardiac Cells Alcohol Alcohol., January 1, 2009; 44(1): 20 - 24. [Abstract] [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]

				G. Chanoit, S. Lee, J. Xi, M. Zhu, R. A. McIntosh, R. A. Mueller, E. A. Norfleet, and Z. Xu Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3{beta} Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1227 - H1233. [Abstract] [Full Text] [PDF]

				E. Murphy and C. Steenbergen Does Inhibition of Glycogen Synthase Kinase Protect in Mice? Circ. Res., August 1, 2008; 103(3): 226 - 228. [Full Text] [PDF]