Cardioprotection mediated by urocortin is dependent on PKCepsilon activation

Lawrence, Kevin M., Kabir, Alamgir M.N., Bellahcene, Mohammed, Davidson, Sean, Mesquita, Rue S., Cao, Xuebin, McCormick, James, Carroll, Christopher J., Chanalaris, Anastasios, Townsend, Paul A., Hubank, Mike, Stephanou, Anastasis, Knight, Richard A., Marber, Michael S. and Latchman, David S. (2005) Cardioprotection mediated by urocortin is dependent on PKCepsilon activation. The FASEB Journal, 19 (7), 831-833. (doi:10.1096/fj.04-2506fje).

Abstract

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 (PKC?) 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 PKC? in vitro and in the Langendorff perfused ex vivo heart. The importance of the PKC? isozyme in cardioprotection and its relationship to cardioprotection produced by Ucn was assessed using PKC?-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 PKC? knockout mice. These findings indicate that the cardioprotective effect of Ucn is dependent upon PKC?.

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