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We have used Affymetrix gene chip technology to look for changes in gene expression caused by a 24 h exposure of rat primary neonatal cardiac myocytes to the cardioprotective agent urocortin. We observed a 2.5-fold down-regulation at both the mRNA and protein levels of a specific calcium-insensitive phospholipase A2 enzyme. Levels of lysophosphatidylcholine, a toxic metabolite of phospholipase A2, were lowered by 30% in myocytes treated with urocortin for 24 h and by 50% with the irreversible iPLA2 inhibitor bromoenol lactone compared with controls. Both 4 h ischemia and ischemia followed by 24 h reperfusion caused a significant increase in lysophosphatidylcholine concentration compared with controls. When these myocytes were pretreated with urocortin, the ischemia-induced increase in lysophosphatidylcholine concentration was significantly lowered. Moreover, co-incubation of cardiac myocytes with urocortin, or the specific phospholipase A2 inhibitor bromoenol lactone, reduces the cytotoxicity produced by lysophosphatidylcholine or ischemia/reperfusion. Similarly, in the intact heart ex vivo we found that cardiac damage measured by infarct size was significantly increased when lysophoshatidylcholine was applied during ischemia, compared with ischemia alone, and that pre-treatment with both urocortin and bromoenol lactone reversed the increase in infarct size. This, to our knowledge, is the first study linking the cardioprotective effect of urocortin to a decrease in a specific enzyme protein and a subsequent decrease in the concentration of its cardiotoxic metabolite.

Type

Journal article

Journal

The FASEB Journal

Publication Date

12/2003

Volume

17

Pages

2313 - 2315

Addresses

Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guilford St., London WC1N 1EH, UK. k.lawrence@ich.ucl.ac.uk

Keywords

Cells, Cultured, Myocytes, Cardiac, Animals, Rats, Myocardial Reperfusion Injury, Pyrones, Naphthalenes, Corticotropin-Releasing Hormone, Phospholipases A, Lysophosphatidylcholines, RNA, Messenger, Cardiotonic Agents, Enzyme Inhibitors, Cell Death, Cell Survival, Gene Expression Regulation, Kinetics, Models, Biological, Phospholipases A2, Group VI Phospholipases A2, Urocortins