TY - JOUR
T1 - Differential actions of cardioprotective agents on the mitochondrial death pathway
AU - Akao, Masaharu
AU - O'Rourke, Brian
AU - Kusuoka, Hideo
AU - Teshima, Yasushi
AU - Jones, Steven P.
AU - Marbán, Eduardo
PY - 2003/2/7
Y1 - 2003/2/7
N2 - We examined the effect of cardioprotective agents on three distinct phases of the H2O2-induced response that leads to loss of mitochondrial membrane potential (ΔΨm) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved ΔΨm, (2) depolarization, the rapid ΔΨm depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoKATP) 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 ΔΨm depolarization but also delayed the onset of ΔΨm 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 mitoKATP channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for ΔΨm 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 mitoKATP 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.
AB - We examined the effect of cardioprotective agents on three distinct phases of the H2O2-induced response that leads to loss of mitochondrial membrane potential (ΔΨm) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved ΔΨm, (2) depolarization, the rapid ΔΨm depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoKATP) 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 ΔΨm depolarization but also delayed the onset of ΔΨm 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 mitoKATP channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for ΔΨm 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 mitoKATP 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.
KW - Cell death
KW - Membrane potential
KW - Mitochondria
KW - Oxidative stress
KW - Potassium channels
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U2 - 10.1161/01.RES.0000051862.16691.F9
DO - 10.1161/01.RES.0000051862.16691.F9
M3 - Article
C2 - 12574147
AN - SCOPUS:0037423675
SN - 0009-7330
VL - 92
SP - 195
EP - 202
JO - Circulation research
JF - Circulation research
IS - 2
ER -