Downregulation of protein kinase C inhibits activation of mitochondrial KATP channels by diazoxide

Yigang Wang, En Takashi, Meifeng Xu, Ahmar Ayub, Muhammad Ashraf

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88 Scopus citations

Abstract

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-α and PKC-δ were translocated to the sarcolemma and that PKC-δ 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-δ to the mitochondria.

Original languageEnglish (US)
Pages (from-to)85-90
Number of pages6
JournalCirculation
Volume104
Issue number1
DOIs
Publication statusPublished - Jul 3 2001
Externally publishedYes

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Keywords

  • Ion channels
  • Ischemia
  • Myocardium
  • Protein kinase C

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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