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1 Department of Laboratory Medicine, Oita Medical University, Oita 879-5593, Japan; and 2 Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
Although mitochondrial ATP-sensitive
potassium (mitoKATP) channels have been reported to reduce
the extent of apoptosis, the critical timing of
mitoKATP channel opening required to protect myocytes
against apoptosis remains unclear. In the present study, we
examined whether the mitoKATP channel serves as a trigger
of cardioprotection against apoptosis induced by oxidative
stress. Apoptosis of cultured neonatal rat cardiomyocytes was
determined by flow cytometry (light scatter and propidium
iodide/annexin V-FITC fluorescence) and by nuclear staining with
Hoechst 33342. Mitochondrial membrane potential (
) was measured
by flow cytometry of cells stained with rhodamine-123 (Rh-123).
Exposure to H2O2 (500 µM) induced
apoptosis, and the percentage of apoptotic cells increased
progressively and peaked at 2 h. This
H2O2-induced apoptosis was associated
with the loss of , and the time course of decrease in Rh-123
fluorescence paralleled that of apoptosis. Pretreatment of
cardiomyocytes with diazoxide (100 µM), a putative
mitoKATP channel opener, for 30 min before exposure to
H2O2 elicited transient and mild depolarization
of and consequently suppressed both apoptosis and
loss after 2-h exposure to H2O2. These
protective effects of diazoxide were abrogated by the
mitoKATP channel blocker 5-hydroxydecanoate (500 µM)
but not by the sarcolemmal KATP channel blocker HMR-1098
(30 µM). Our results suggest for the first time that
diazoxide-induced opening of mitoKATP channels triggers
cardioprotection against apoptosis induced by oxidative stress
in rat cardiomyocytes.
cardiomyocytes; mitochondria; mitochondrial membrane potential; preconditioning
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