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Urocortin (Ucn) is an endogenous cardioprotective agent that protects against the damaging effects of ischemia and reperfusion injury in vitro and in vivo. We have found that the mechanism of action of Ucn involves both acute activation of specific target molecules, and using Affymetrix (Santa Clara, CA) gene chip technology, altered gene expression of different end effector molecules. Here, from our gene chip data, we show that after a 24 h exposure to Ucn, there was a specific increase in mRNA and protein levels of the protein kinase C epsilon (PKCepsilon) isozyme in primary rat cardiomyocytes compared with untreated cells and in the Langendorff perfused ex vivo heart. Furthermore, a short 10 min exposure of these cells to Ucn caused a specific translocation/activation of PKCepsilon in vitro and in the Langendorff perfused ex vivo heart. The importance of the PKCepsilon isozyme in cardioprotection and its relationship to cardioprotection produced by Ucn was assessed using PKCepsilon-specific inhibitor peptides. The inhibitor peptide, when introduced into cardiomyocytes, caused an increase in apoptotic cell death compared with control peptide after ischemia and reperfusion. When the inhibitor peptide was present with Ucn, the cardioprotective effect of Ucn was lost. This loss of cardioprotection by Ucn was also seen in whole hearts from PKCepsilon knockout mice. These findings indicate that the cardioprotective effect of Ucn is dependent upon PKCepsilon.

Original publication

DOI

10.1096/fj.04-2506fje

Type

Journal article

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Date

05/2005

Volume

19

Pages

831 - 833

Addresses

Medical Molecular Biology Unit, Institute of Child Health, University College, London, UK. k.lawrence@ich.ucl.ac.uk

Keywords

Mitochondria, Heart, Myocytes, Cardiac, Animals, Animals, Newborn, Mice, Knockout, Mice, Rats, Rats, Sprague-Dawley, Corticotropin-Releasing Hormone, RNA, Messenger, Cardiotonic Agents, Protein Kinase Inhibitors, In Situ Nick-End Labeling, Apoptosis, Enzyme Activation, Protein Kinase C-epsilon, Urocortins