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CARDIOVASCULAR

Peripheral Benzodiazepine Receptor-Induced Myocardial Protection is Mediated by Inhibition of Mitochondrial Membrane Permeabilization

Institut National de la Santé et de la Recherche Médicale, Unité 841, Créteil, France (R.Z., A.B., D.M.); Laboratoire de Pharmacologie, Université Paris 12, Facultéde Médecine Institut de Formation de Recherche 10, Créteil, France (F.N.O., R.Z., A.B., D.M.); and Plate-forme petit animal, Facultéde Médecine IFR 10, Créteil, France (R.S.)

Opening of the permeability transition pore (PTP) is a key event in ischemia-reperfusion injury and several ligands of the peripheral benzodiazepine receptor (PBR), a mitochondrial outer membrane protein possibly associated with PTP, have been demonstrated as potent cardioprotective agents. Here, we investigated the mechanisms by which the specific PBR ligand 4'-chlorodiazepam (CDZ) protected the myocardium against ischemia-reperfusion. In either global or regional models of myocardial ischemia-reperfusion in rats, CDZ reduced infarct size in a dose-dependent manner (e.g., 11 ± 1% of the area at risk at 10 mg/kg versus 31 ± 3% in control; p < 0.05) and to a similar extent as ischemic or diazoxide-induced preconditioning. CDZ (10 mg/kg) reduced apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining), restored mitochondrial recovery, improved oxidative phosphorylation parameters, and reduced mitochondrial membrane permeabilization with inhibition of cytochrome c and apoptosis-inducing factor releases. CDZ increased the resistance of mitochondria to Ca²⁺-induced PTP opening. All these cardioprotective effects of CDZ were associated with an improved stabilization of the association of Bcl-2 with the mitochondrial membrane and inhibition of the association of a cytosolic fragment of Bax, occurring during ischemia-reperfusion, with the outer mitochondrial membrane. In addition, the PTP opener atractyloside (20 µM) and the Bcl-2 inhibitor ethyl-2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1) (20 µM) abrogated CDZ-induced reduction of infarct size. These results demonstrate that PBR occupancy by CDZ renders the heart more resistant to ischemia-reperfusion injury by limiting mitochondrial membrane permeabilization. This is due to a reorganization of the balance between pro- and antiapoptotic proteins of the Bcl-2 family proteins at the level of mitochondrial membranes.

Address correspondence to: Dr. Alain Berdeaux, INSERM U841, équipe 3, Facultéde Médecine de Paris XII, 8 rue du Général Sarrail, F-94010, Créteil, France. E-mail: berdeaux{at}creteil.inserm.fr

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				F. N. Obame, C. Plin-Mercier, R. Assaly, R. Zini, J. L. Dubois-Rande, A. Berdeaux, and D. Morin Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3{beta}, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 252 - 258. [Abstract] [Full Text] [PDF]