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
|