Protein kinase C inhibitors produce mitochondrial flavoprotein oxidation in cardiac myocytes.
Inhibition of protein kinase C (PKC) antagonizes ischemic preconditioning of myocardium. Opening of mitochondrial adenosine triphosphate (ATP)-dependent potassium (mitoK(ATP)) channels and subsequent oxidation of mitochondria are known to contribute to ischemic preconditioning. We therefore tested the effects of PKC inhibitors on flavoprotein oxidation, measured by flavoprotein fluorescence, as an index of mitoK(ATP) activity in ventricular myocytes from guinea pigs. The PKC inhibitors chelerythrine (1 and 5 microM) and bisindolylmaleimide (100 and 400 nM) strongly increased flavoprotein oxidation in a dose-dependent manner. Specific inhibition of PKC-delta by rottlerin produced persistent flavoprotein oxidation. Inhibition of the production of inositol (1,4,5)-triphosphate by neomycin (0.5 mM) abolished chelerythrine- but not rottlerin-induced flavoprotein oxidation. Inhibition of PKC promotes flavoprotein oxidation via production of inositol (1,4,5)-triphosphate, possibly through the PKC-delta isoform. We speculate that although a certain degree of mitochondrial flavoprotein oxidation causes cardioprotective effects, excessive and/or persistent oxidation abolishes any beneficial actions. Instead of a simple mediator, PKC may act as a regulator of the mitoK(ATP) channel to prevent excessive mitochondrial oxidation.
Kohro
Shinji
S
Departments 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.
Hogan
Quinn H
QH
Warltier
David C
DC
Bosnjak
Zeljko J
ZJ
D000098:Acetophenones / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D001578:Benzopyrans / Q000494:pharmacology; D002138:Calibration; D002469:Cell Separation; D005260:Female; D005420:Flavoproteins / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009355:Neomycin / Q000494:pharmacology; D010084:Oxidation-Reduction; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051745:Protein Kinase C-delta; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013050:Spectrometry, Fluorescence
D000098:Acetophenones; D000470:Alkaloids; D053119:Benzophenanthridines; D001578:Benzopyrans; D005420:Flavoproteins; D007211:Indoles; D008301:Maleimides; D010617:Phenanthridines; D011500:Protein Synthesis Inhibitors; D015544:Inositol 1,4,5-Trisphosphate; C085746:rottlerin; C016299:chelerythrine; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D009355:Neomycin; C088060:bisindolylmaleimide