Published online before print May 19, 2008, doi: 10.1161/CIRCULATIONAHA.107.755066
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(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
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
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Clinical Summaries
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