Received for publication April 12, 2007.
Revised July 18, 2007.
Accepted for publication July 18, 2007.

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

Abstract

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 vs 31±3% in control, p<0.05) and to a similar extent as ischemic or diazoxide-induced preconditioning. CDZ (10 mg/kg) reduced apoptosis (TUNEL staining), restored mitochondrial recovery, improved oxidative phosphorylation parameters and reduced mitochondrial membrane permeabilization with inhibition of cytochrome c and apoptosis inducing factor (AIF) 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, appearing during ischemia-reperfusion, with the outer mitochondrial membrane. In addition, the PTP opener atractyloside (20 µM) and the Bcl-2 inhibitor 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 anti-apoptotic proteins of the Bcl-2 family proteins at the level of mitochondrial membranes.

Key words: Bcl-2 family proteins, heart, ischemia-reperfusion, mitochondria, peripheral benzodiazepine receptor, permeability transition pore

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