Gomez 2008 Circulation
Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M (2008) Inhibition of GSK3beta by postconditioning is required to prevent opening of the mitochondrial permeability transition pore during reperfusion. Circulation 117:2761-68. |
Gomez L, Paillard M, Thibault H, Derumeaux G, Ovize M (2008) Circulation
Abstract: BackgroundβOpening of the mitochondrial permeability transition pore (mPTP) is a crucial event in lethal reperfusion injury. Phosphorylation (inhibition) of glycogen synthase kinase-3Ξ² (GSK3Ξ²) has been involved in cardioprotection. We investigated whether phosphorylated GSK3Ξ² may protect the heart via the inhibition of mPTP opening during postconditioning.
Methods and ResultsβWild-type and transgenic GSK3Ξ²-S9A mice (the cardiac GSK3Ξ² activity of which cannot be inactivated) underwent 60 minutes of ischemia and 24 hours of reperfusion. At reperfusion, wild-type and GSK3Ξ²-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 GSK3Ξ² inhibitor SB216763 (SB21; 70 Β΅g/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 39Β±2%, 35Β±5%, and 37Β±4%, respectively, versus 58Β±5% of the area at risk in control mice (P<0.05). In GSK3Ξ²-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 GSK3Ξ²-S9A mice.
ConclusionβThese results suggest that S9-phosphorylation of GSK3Ξ² is required for postconditioning and likely acts by inhibiting the opening of the mitochondrial permeability transition pore. β’ Keywords: Myocardial infarction
Labels: MiParea: Pharmacology;toxicology
Stress:Ischemia-reperfusion;preservation"Ischemia-reperfusion;preservation" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Permeability transition Organism: Mouse Tissue;cell: Heart Preparation: Isolated mitochondria
Coupling state: OXPHOS
HRR: Oxygraph-2k
Spectrophotometry; Spectrofluorimetry