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

Townsend, PA; Davidson, SM; Clarke, SJ; Khaliulin, I; Carroll, CJ; Scarabelli, TM; Knight, RA; ... Halestrap, AP; + view all (2007) Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress. AM J PHYSIOL-HEART C , 293 (2) H928 - H938. 10.1152/ajpheart.01135.2006.

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Abstract

Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress. Am J Physiol Heart Circ Physiol 293: H928 - H938, 2007. First published May 4, 2007; doi:10.1152/ajpheart.01135.2006. - 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-[H-3] 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.

Type: Article
Title: Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stress
DOI: 10.1152/ajpheart.01135.2006
Keywords: mitochondria, oxygen radicals, peptide hormones, K-ATP CHANNEL, ADENINE-NUCLEOTIDE TRANSLOCASE, CARDIAC MYOCYTES, ISCHEMIA-REPERFUSION, CYCLOSPORINE-A, EPSILON ACTIVATION, GENE-EXPRESSION, MURINE HEART, PKC-EPSILON, DELTA-PKC
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH - Directors Office
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Genetics and Genomic Medicine Prog
URI: http://discovery.ucl.ac.uk/id/eprint/120364
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