Document Detail


Role of Ca(2+)-independent phospholipase A(2) in the regulation of inducible nitric oxide synthase in cardiac myocytes.
MedLine Citation:
PMID:  10642306     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have previously shown that the regulation by interleukin-1beta (IL-1beta) of inducible nitric oxide synthase (iNOS) involves phospholipase A(2) (PLA(2)) metabolites in neonatal ventricular myocytes. Based on studies in which ONO-RS-082 is used to inhibit secretory PLA(2) and methyl arachidonyl fluorophosphonate is used to inhibit cytosolic PLA(2), our data suggest that a secretory PLA(2) metabolite was involved in the regulation by IL-1beta of iNOS. In addition, a third PLA(2) isoform, which is Ca(2+) independent (iPLA(2)), has also been detected in cardiac myocytes and shown to be regulated by cytokines. We tested whether iPLA(2) metabolites are involved in the regulation by IL-1beta of iNOS with the use of bromoenol lactone (BEL), a specific and irreversible inhibitor of iPLA(2). For this, we measured IL-1beta-stimulated nitrite (NOx) production with use of the Griess reagent, prostaglandin E(2) (PGE(2)) production with use of an enzyme immunoassay, and arachidonic acid release in the presence and absence of BEL. We also detected iNOS and iPLA(2) proteins by Western blotting. Treatment with IL-1beta (5 ng/mL) for 24 hours stimulated NOx production by 8-fold and iNOS protein levels by at least 10-fold. In addition, arachidonic acid release was increased by 1.6-fold and PGE(2) production was increased by 300-fold. When neonatal ventricular myocytes were treated with 10 micromol/L BEL, both IL-1beta-stimulated PGE(2) production and arachidonic acid release were inhibited. BEL inhibited IL-1beta-stimulated NOx production and iNOS protein by 88% and 93%, respectively. Lysophosphatidic acid, but not arachidonic acid or lysophosphatidylcholine, stimulated iNOS expression. Our results indicate that an iPLA(2) metabolite, perhaps lysophosphatidic acid, may be involved in the IL-1beta-signaling pathway, regulating the synthesis of iNOS.
Authors:
E Isenović; M C LaPointe
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Hypertension     Volume:  35     ISSN:  0194-911X     ISO Abbreviation:  Hypertension     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-02-07     Completed Date:  2000-02-07     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  249-54     Citation Subset:  IM    
Affiliation:
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI 48202, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Arachidonic Acid / pharmacology
Calcium / metabolism
Cells, Cultured
Dinoprostone / metabolism
Heart Ventricles / cytology,  enzymology
Interleukin-1 / pharmacology
Lysophosphatidylcholines / pharmacology
Lysophospholipids / pharmacology
Muscle Fibers, Skeletal / cytology,  drug effects,  enzymology*
Myocardium / cytology,  enzymology*
Naphthalenes / pharmacology
Nitric Oxide / biosynthesis
Nitric Oxide Synthase / biosynthesis,  metabolism*
Nitric Oxide Synthase Type II
Phosphodiesterase Inhibitors / pharmacology
Phospholipases A / antagonists & inhibitors,  metabolism*
Pyrones / pharmacology
Rats
Rats, Sprague-Dawley
Grant Support
ID/Acronym/Agency:
HL-03188/HL/NHLBI NIH HHS; HL-28982/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Interleukin-1; 0/Lysophosphatidylcholines; 0/Lysophospholipids; 0/Naphthalenes; 0/Phosphodiesterase Inhibitors; 0/Pyrones; 10102-43-9/Nitric Oxide; 363-24-6/Dinoprostone; 506-32-1/Arachidonic Acid; 7440-70-2/Calcium; 88070-98-8/6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.14.13.39/Nos2 protein, rat; EC 3.1.1.-/Phospholipases A

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