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Papers In Press, published online ahead of print October 24, 2001
Medicinal Pharmacology, Osaka University, Suita, Osaka 565-0871
Corresponding Author: matsuda{at}phs.osaka-u.ac.jp
Reperfusion of cultured astrocytes with normal medium after exposure to hydrogen peroxide (H2O2)-containing medium causes apoptosis. We have recently shown that ibudilast, which has been used for bronchial asthma and cerebrovascular disorders, attenuated the H2O2-induced apoptosis of astrocytes via cGMP signaling pathway. This study examined the mechanism underlying the protective effect of cGMP. The membrane-permeable cGMP analog dibutyryl-cGMP attenuated the H2O2-induced decrease in cell viability, DNA ladder formation, nuclear condensation, reduction of the mitochondrial membrane potential, cytochrome c release from mitochondria and caspase-3 activation in a dose-dependent manner in cultured astrocytes. These effects of dibutyryl-cGMP were almost completely inhibited by the cGMP-dependent protein kinase (PKG) inhibitor KT5823. In isolated rat brain mitochondria, cGMP in the presence of cytosolic extract from astrocytes inhibited the mitochondrial permeability transition pore (PTP) as determined by monitoring Ca2+-induced mitochondrial swelling. This ability of the cytosolic extract was inactivated by heat treatment and was mimicked by exogenous PKG. The effect of cGMP on the mitochondrial swelling was blocked by KT5823. The PTP inhibitors cyclosporin A and bongkrekic acid prevented the H2O2-induced decrease in cell viability and caspase-3 activation. These findings demonstrate that cGMP inhibits the mitochondrial PTP via the activation of PKG, and the prevention of mitochondrial dysfunction contributes to its anti-apoptotic effect.
J. Biol. Chem, 10.1074/jbc.M108622200
Submitted on September 6, 2001
Revised on October 15, 2001
Accepted on October 24, 2001
Anti-apoptotic effect of cGMP in cultured astrocytes: Inhibition by cGMP-dependent protein kinase of mitochondrial permeable transition pore
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