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CARDIOVASCULAR

N⁶-(3-Iodobenzyl)-adenosine-5'-N-methylcarboxamide Confers Cardioprotection at Reperfusion by Inhibiting Mitochondrial Permeability Transition Pore Opening via Glycogen Synthase Kinase 3

Department of Anesthesiology, the University of North Carolina, Chapel Hill, North Carolina

Although the adenosine A₃ receptor agonist N⁶-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (IB-MECA) has been reported to be cardioprotective at reperfusion, little is known about the mechanisms underlying the protection. We hypothesized that IB-MECA may protect the heart at reperfusion by preventing the opening of mitochondrial permeability transition pore (mPTP) through inactivation of glycogen synthase kinase (GSK) 3. IB-MECA (1 µM) applied during reperfusion reduced infarct size in isolated rat hearts, an effect that was abrogated by the selective A₃ receptor antagonist 1,4-dihydro-2-methyl-6-phenyl-4-(phenylethynyl)-3,5-pyridinedicarboxylic acid 3-ethyl-5-[(3-nitrophenyl)-methyl]ester (MRS1334) (100 nM). The effect of IB-MECA was abrogated by the mPTP opener atractyloside (20 µM), implying that the action of IB-MECA may be mediated by inhibition of the mPTP opening. In cardiomyocytes, IB-MECA attenuated oxidant-induced loss of mitochondrial membrane potential (_m), which was reversed by MRS1334. IB-MECA also reduced Ca²⁺-induced mitochondrial swelling. IB-MECA enhanced phosphorylation of GSK-3 (Ser⁹) upon reperfusion, and the GSK-3 inhibitor 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763) (3 µM) mimicked the protective effect of IB-MECA by attenuating both infarction and the loss of _m. In addition, the effect of IB-MECA on GSK-3 was reversed by wortmannin (100 nM), and IB-MECA was shown to enhance Akt phosphorylation upon reperfusion. In contrast, rapamycin (2 nM) failed to affect GSK-3 phosphorylation by IB-MECA, and IB-MECA did not alter phosphorylation of either mTOR (Ser²⁴⁴⁸) or 70s6K (Thr³⁸⁹). Taken together, these data suggest that IB-MECA prevents myocardial reperfusion injury by inhibiting the mPTP opening through the inactivation of GSK-3 at reperfusion. IB-MECA-induced GSK-3 inhibition is mediated by the PI3-kinase/Akt signal pathway but not by the mTOR/p70s6K pathway.

Address correspondence to: Dr. Zhelong Xu, Department of Anesthesiology, CB 7010, University of North Carolina, Chapel Hill, NC 27599. E-mail: zxu{at}aims.unc.edu

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