(Circulation. 2001;104:85.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Downregulation of Protein Kinase C Inhibits Activation of Mitochondrial KATP Channels by Diazoxide
From the Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to Muhammad Ashraf, PhD, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Bethesda Ave, Cincinnati, OH 45267-0529. E-mail Muhammad.Ashraf{at}uc.edu
Background—The mitochondrial KATP (mitoKATP) channel has been shown to confer short- and long-term cardioprotection against prolonged ischemia via protein kinase C (PKC) signaling pathways. However, the exact association between PKC or its isoforms and mitoKATP channels has not yet been clarified. The present study tested the hypothesis that the activity and translocation of PKC to the mitochondria are important for cardiac protection elicited by mitoKATP channels.
Methods and Results—PKC
was downregulated by prolonged (24-hour) treatment with phorbol
12-myristate 13-acetate (4 µg/kg body weight) before
subsequent experiments in rats. Langendorff-perfused rat hearts were
subjected to 40 minutes of ischemia followed by 30 minutes of
reperfusion. Effects of PKC downregulation on the activation of
mitoKATP channels and other interventions on
hemodynamic, biochemical, and pathological changes were
assessed. Subcellular localization of PKC isoforms by Western blot
analysis and immunocytochemistry demonstrated that PKC-
and
PKC-
were translocated to the sarcolemma and that PKC- was
translocated to the mitochondria after diazoxide treatment. In hearts
treated with diazoxide (80 µmol/L), a significant improvement in
cardiac function and an attenuation of cell injury were observed. In
PKC-downregulated hearts, protection was abolished because
mitoKATP channels could not be activated
by diazoxide.
Conclusions—These data
suggest that PKC activation is required for the opening of
mitoKATP channels during protection against
ischemia and that this effect is linked to isoform-specific
translocation of PKC- to the mitochondria.
Key Words: ischemia • ion channels • protein kinase C • myocardium
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