A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia-induced cell death.
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 epsilon-protein kinase C activation, a 2. 8-fold increase in delta-protein kinase C activation, and no increase in betaI-protein kinase C activation. 4beta-Phorbol 12-myristate 13-acetate mimicked hypoxic preconditioning, increasing myocyte survival after prolonged hypoxia by 34% compared with control. We previously identified an epsilon-protein kinase C-selective antagonist, epsilonV1-2 peptide, that inhibits epsilon-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). epsilonV1-2 peptide abolished hypoxic preconditioning and phorbol ester-mediated cardiac protection. Therefore, preconditioning can be induced in this culture model, and activation of epsilon-protein kinase C is critical for cardiac myocyte protection.
Gray
M O
MO
Cardiology Section, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Karliner
J S
JS
Mochly-Rosen
D
D
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000502:physiology; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000166:cytology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D051744:Protein Kinase C-epsilon; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D007527:Isoenzymes; D010446:Peptide Fragments; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D013755:Tetradecanoylphorbol Acetate