The cardioprotective effect of urocortin during ischaemia/reperfusion involves the prevention of mitochondrial damage.
We have previously shown, using Affymetrix gene chip technology, that urocortin induces the expression of several diverse genes in cardiac myocytes. An ATP sensitive inwardly rectifying potassium channel, Katp (Kir6.1), the enzyme calcium independent phospholipase A2 (iPLA2), and protein kinase C epsilon (PKCepsilon) and that these genes are involved in the cardioprotective mechanism of action of urocortin. Here we demonstrate that these gene products are localized to cardiac myocyte mitochondria and for the first time show that urocortin protects cardiac myocytes from ischaemia/reperfusion induced cell death by preventing mitochondrial damage. Using pharmacological agents to Katp channels and iPLA2 and synthetic peptide inhibitors of PKCepsilon, we go on to demonstrate that these three gene products are involved in the urocortin induced protection of cardiac myocyte mitochondria. These proteins may interact at the mitochondria to produce the protective effect.
Lawrence
Kevin M
KM
Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK. k.lawrence@ich.ucl.ac.uk
Townsend
Paul A
PA
Davidson
Sean M
SM
Carroll
Christopher J
CJ
Eaton
Simon
S
Hubank
Mike
M
Knight
Richard A
RA
Stephanou
Anastasis
A
Latchman
David S
DS
D000447:Aldehydes; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control*; D012235:Rhodamines; D054832:Urocortins
D000447:Aldehydes; D002316:Cardiotonic Agents; D024661:Potassium Channels, Inwardly Rectifying; D012235:Rhodamines; D054832:Urocortins; C111472:mitotracker green FM; C401833:tetramethylrhodamine methyl ester; D003346:Corticotropin-Releasing Hormone; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D010741:Phospholipases A; D054467:Phospholipases A2