Urocortin protects cardiac myocytes from ischemia/reperfusion injury by attenuating calcium-insensitive phospholipase A2 gene expression.

Abstract

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.

• Authors: K M Lawrence, T M Scarabelli, L Turtle, A Chanalaris, P A Townsend, C J Carroll, M Hubank, A Stephanou, R A Knight, D S Latchman
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 17 Issue 15 Pg. 2313-5 (Dec 2003) ISSN: 1530-6860 [Electronic] United States
• PMID: 14563694 (Publication Type: Journal Article)

Chemical References

• Cardiotonic Agents
• Enzyme Inhibitors
• Lysophosphatidylcholines
• Naphthalenes
• Pyrones
• RNA, Messenger
• Urocortins
• 6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one
• Corticotropin-Releasing Hormone
• Phospholipases A
• Group VI Phospholipases A2
• Phospholipases A2

Topics

• Animals
• Cardiotonic Agents (metabolism, pharmacology)
• Cell Death
• Cell Survival (drug effects)
• Cells, Cultured
• Corticotropin-Releasing Hormone (metabolism, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation
• Group VI Phospholipases A2
• Kinetics
• Lysophosphatidylcholines (metabolism, pharmacology)
• Models, Biological
• Myocardial Reperfusion Injury (enzymology)
• Myocytes, Cardiac (drug effects, enzymology, metabolism)
• Naphthalenes (pharmacology)
• Phospholipases A (antagonists & inhibitors, genetics, metabolism)
• Phospholipases A2
• Pyrones (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Urocortins