Differential actions of cardioprotective agents on the mitochondrial death pathway.
We examined the effect of cardioprotective agents on three distinct phases of the H2O2-induced response that leads to loss of mitochondrial membrane potential (DeltaPsi(m)) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved DeltaPsi(m), (2) depolarization, the rapid DeltaPsi(m) depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel opener diazoxide markedly decreased the likelihood that cells would undergo priming: many mitochondria remained fully polarized and morphologically intact. Diazoxide not only decreased the number of cells undergoing DeltaPsi(m) depolarization but also delayed the onset of DeltaPsi(m) loss, whereas it did not change the duration of depolarization in unprotected cells. The adenine nucleotide translocase inhibitor bongkrekic acid mimicked the effect of diazoxide to suppress priming, except that its effects were not blocked by the mitoK(ATP) channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for DeltaPsi(m) depolarization nor mitochondrial morphological changes were affected. However, CsA slowed the process of depolarization and blunted its severity. Importantly, coapplication of diazoxide and CsA exhibited additive effects, improving the efficacy of protection. Activation of mitoK(ATP) channels suppresses the cell death process at its earliest stage, by preserving mitochondrial integrity during oxidative stress. By virtue of its pharmacology and its phenotypic consequences, this mode of action is distinguishable from that of other cardioprotective interventions.
Akao
Masaharu
M
Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, Md 21205, USA.
O'Rourke
Brian
B
Kusuoka
Hideo
H
Teshima
Yasushi
Y
Jones
Steven P
SP
Marbán
Eduardo
E
D001865:Bongkrekic Acid / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D001865:Bongkrekic Acid; D016572:Cyclosporine; D003981:Diazoxide