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Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress

Townsend, Paul A., Davidson, Sean M., Clarke, Samantha J., Khaliulin, Igor, Carroll, Christopher J., Scarabelli, Tiziano M., Knight, Richard A., Stephanou, Anastasis, Latchman, David S. and Halestrap, Andrew P. (2007) Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress American Journal of Physiology: Heart and Circulatory Physiology, 293, (2), H928-H938. (doi:10.1152/ajpheart.01135.2006).

Record type: Article

Abstract

Urocortin (UCN) protects hearts against ischemia and reperfusion injury whether given before ischemia or at reperfusion. Here we investigate the roles of PKC, reactive oxygen species, and the mitochondrial permeability transition pore (MPTP) in mediating these effects. In Langendorff-perfused rat hearts, acute UCN treatment improved hemodynamic recovery during reperfusion after 30 min of global ischemia; this was accompanied by less necrosis (lactate dehydrogenase release) and MPTP opening (mitochondrial entrapment of 2-[(3)H]deoxyglucose). UCN pretreatment protected mitochondria against calcium-induced MPTP opening, but only if the mitochondria had been isolated from hearts after reperfusion. These mitochondria also exhibited less protein carbonylation, suggesting that UCN decreases levels of oxidative stress. In isolated adult and neonatal rat cardiac myocytes, both acute (60 min) and chronic (16 h) treatment with UCN reduced cell death following simulated ischemia and re-oxygenation. This was accompanied by less MPTP opening as measured using tetramethylrhodamine methyl ester. The level of oxidative stress during reperfusion was reduced in cells that had been pretreated with UCN, suggesting that this is the mechanism by which UCN desensitizes the MPTP to reperfusion injury. Despite the fact that we could find no evidence that either PKC-epsilon or PKC-alpha translocate to the mitochondria following acute UCN treatment, inhibition of PKC with chelerythrine eliminated the effect of UCN on oxidative stress. Our data suggest that acute UCN treatment protects the heart by inhibiting MPTP opening. However, the mechanism appears to be indirect, involving a PKC-mediated reduction in oxidative stress.

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Published date: August 2007
Keywords: mitochondria, oxygen radicals, peptide hormones

Identifiers

Local EPrints ID: 60335
URI: http://eprints.soton.ac.uk/id/eprint/60335
ISSN: 0363-6135
PURE UUID: eb0760d7-fc84-4395-9600-c269f2d6c921

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Date deposited: 18 Nov 2008
Last modified: 17 Jul 2017 14:23

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Contributors

Author: Paul A. Townsend
Author: Sean M. Davidson
Author: Samantha J. Clarke
Author: Igor Khaliulin
Author: Christopher J. Carroll
Author: Tiziano M. Scarabelli
Author: Richard A. Knight
Author: Anastasis Stephanou
Author: David S. Latchman
Author: Andrew P. Halestrap

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