© 1999 American Heart Association, Inc.
Original Contribution |
Role of Protein Kinase C in Mitochondrial KATP Channel–Mediated Protection Against Ca2+ Overload Injury in Rat Myocardium
From the Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Ohio.
Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0529.
Abstract—Growing evidence
exists that ATP-sensitive mitochondrial potassium channels
(MitoKATP channel) are a major contributor to the cardiac
protection against ischemia. Given the importance of
mitochondria in the cardiac cell, we tested whether the potent and
specific opener of the MitoKATP channel diazoxide
attenuates the lethal injury associated with Ca2+overload.
The specific aims of this study were to test whether protection by
diazoxide is mediated by MitoKATP channels; whether
diazoxide mimics the effects of Ca2+ preconditioning; and
whether diazoxide reduces Ca2+ paradox (PD) injury via
protein kinase C (PKC) signaling pathways. Langendorff-perfused rat
hearts were subjected to the Ca2+ PD (10 minutes of
Ca2+ depletion followed by 10 minutes of Ca2+
repletion). The effects of the MitoKATP channel and other
interventions on functional, biochemical, and pathological changes in
hearts subjected to Ca2+ PD were assessed. In hearts
treated with 80 µmol/L diazoxide, left ventricular
end-diastolic pressure and coronary flow were
significantly preserved after Ca2+ PD; peak lactate
dehydrogenase release was also significantly decreased, although ATP
content was less depleted. The cellular structures were well preserved,
including mitochondria and intercalated disks in diazoxide-treated
hearts compared with nontreated Ca2+ PD hearts. The
salutary effects of diazoxide on the Ca2+ PD injury were
similar to those in hearts that underwent Ca2+
preconditioning or pretreatment with phorbol 12-myristate
13-acetate before Ca2+ PD. The addition of sodium
5-hydroxydecanoate, a specific MitoKATP channel
inhibitor, or chelerythrine chloride, a PKC
inhibitor, during diazoxide pretreatment completely
abolished the beneficial effects of diazoxide on the Ca2+
PD. Blockade of Ca2+ entry during diazoxide treatment by
inhibiting L-type Ca2+ channel with verapamil
or nifedipine also completely reversed the beneficial
effects of diazoxide on the Ca2+ PD. PKC-
was
translocated to the mitochondria, intercalated disks, and nuclei of
myocytes in diazoxide-pretreated hearts, and PKC-
and PKC-
were
translocated to sarcolemma and intercalated disks, respectively. This
study suggests that the effect of the MitoKATP channel is
mediated by PKC-mediated signaling pathway.
Key Words: K+ channel • Ca2+ paradox • Ca2+ preconditioning • protein kinase C • diazoxide
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