A Selective ε-Protein Kinase C Antagonist Inhibits Protection of Cardiac Myocytes from Hypoxia-induced Cell Death

• Published in: The Journal of biological chemistry Vol. 272; no. 49; pp. 30945 - 30951
• Main Authors: Gray, Mary O., Karliner, Joel S., Mochly-Rosen, Daria
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-12-1997
• Subjects: Animals; Biological Transport - drug effects; Cell Death - drug effects; Cell Hypoxia - drug effects; Cells, Cultured; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Heart - drug effects; HSP70 Heat-Shock Proteins - metabolism; Ischemic Preconditioning, Myocardial; Isoenzymes - antagonists & inhibitors; Isoenzymes - physiology; Microscopy, Fluorescence; Myocardium - cytology; Peptide Fragments - pharmacology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Protein Kinase C-epsilon; Rats; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.272.49.30945

Protein kinase C activation is thought to protect cardiac tissue from subsequent ischemic injury by a process termed preconditioning. The protein kinase C isozyme that mediates preconditioning has not yet been identified. Using a cell culture model of hypoxic preconditioning, we found that cardiac myocyte viability after 9 h of hypoxia was increased by more than 50% over control. Preconditioning activated protein kinase C isozymes as evidenced by translocation from one cell compartment to another as follows: there was a 2.1-fold increase in ε-protein kinase C activation, a 2.8-fold increase in δ-protein kinase C activation, and no increase in βI-protein kinase C activation. 4β-Phorbol 12-myristate 13-acetate mimicked hypoxic preconditioning, increasing myocyte survival after prolonged hypoxia by 34% compared with control. We previously identified an ε-protein kinase C-selective antagonist, εV1-2 peptide, that inhibits ε-protein kinase C translocation and function in cardiac myocytes (Johnson, J. A., Gray, M. O., Chen, C.-H., and Mochly-Rosen, D. (1996) J. Biol. Chem. 271, 24962–24966). εV1-2 peptide abolished hypoxic preconditioning and phorbol ester-mediated cardiac protection. Therefore, preconditioning can be induced in this culture model, and activation of ε-protein kinase C is critical for cardiac myocyte protection.