This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Kohro, S. Articles by Bosnjak, Z. J. Search for Related Content PubMed PubMed Citation Articles by Kohro, S. Articles by Bosnjak, Z. J. Related Collections Heart Pharmacology

---

CARDIOVASCULAR ANESTHESIA

Protein Kinase C Inhibitors Produce Mitochondrial Flavoprotein Oxidation in Cardiac Myocytes

Shinji Kohro, MD PhD^*, Quinn H. Hogan, MD^*,||, David C. Warltier, MD PhD^*,,,||, and Zeljko J. Bosnjak, PhD^*,

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

Address correspondence and reprint requests to Quinn H. Hogan, MD, Anesthesiology Research, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Address e-mail to qhogan{at}mcw.edu

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 µM) and bisindolylmaleimide (100 and 400 nM) strongly increased flavoprotein oxidation in a dose-dependent manner. Specific inhibition of PKC- 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- 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.

IMPLICATIONS: Inhibition of protein kinase C (PKC) blocks ischemic and anesthetic preconditioning of the myocardium. We observed that PKC inhibition produces intense oxidation of mitochondria by a pathway involving inositol triphosphate. This may indicate that PKC modulates adenosine triphosphate-sensitive K channels to prevent injurious mitochondrial oxidation.

This article has been cited by other articles:

				K. Przyklenk, M. Maynard, and P. Whittaker Reduction of infarct size with D-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial KATP channels Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H830 - H836. [Abstract] [Full Text] [PDF]