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Protein kinase C inhibitors produce mitochondrial flavoprotein oxidation in cardiac myocytes

Shinji Kohro1, Quinn H Hogan, David C Warltier

  • 1Departments of *Anesthesiology, †Physiology, ‡Pharmacology, and §Medicine (Division of Cardiovascular Diseases), Medical College of Wisconsin, Milwaukee; and ∥ Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin.

Anesthesia and Analgesia
|October 27, 2004
PubMed

Insights

Inhibiting protein kinase C (PKC) increases mitochondrial flavoprotein oxidation, indicating mitochondrial ATP-dependent potassium channel activity. This effect is mediated by inositol trisphosphate, suggesting PKC regulates mitochondrial oxidation.

Area of Science:

  • Cardiovascular Science
  • Mitochondrial Biology
  • Cell Signaling

Background:

  • Protein kinase C (PKC) inhibition antagonizes ischemic preconditioning of the myocardium.
  • Mitochondrial ATP-dependent potassium (mitoK(ATP)) channels and mitochondrial oxidation are key to ischemic preconditioning.

Purpose of the Study:

  • To investigate the effects of PKC inhibitors on flavoprotein oxidation as an index of mitoK(ATP) channel activity in guinea pig ventricular myocytes.
  • To elucidate the role of PKC in regulating mitochondrial function during preconditioning.

Main Methods:

  • Measurement of flavoprotein oxidation using flavoprotein fluorescence in ventricular myocytes.
  • Application of various PKC inhibitors (e.g., chelerythrine, bisindolylmaleimide, rottlerin) and inositol trisphosphate production inhibitors (e.g., neomycin).

Main Results:

  • PKC inhibitors dose-dependently increased flavoprotein oxidation.
  • Specific inhibition of PKC-delta isoform by rottlerin led to persistent flavoprotein oxidation.
  • Neomycin abolished chelerythrine-induced, but not rottlerin-induced, flavoprotein oxidation, implicating inositol trisphosphate.

Conclusions:

  • PKC inhibition promotes flavoprotein oxidation, potentially via inositol trisphosphate and the PKC-delta isoform.
  • While some mitochondrial oxidation is cardioprotective, excessive oxidation can be detrimental.
  • PKC may function as a regulator of mitoK(ATP) channels to prevent excessive mitochondrial oxidation, rather than a simple mediator.

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