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(Hypertension. 2000;35:249.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Role of Ca²⁺-Independent Phospholipase A₂ in the Regulation of Inducible Nitric Oxide Synthase in Cardiac Myocytes

Esma Isenovi; Margot C. LaPointe

From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.

Correspondence to Dr Margot C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail mclapointe{at}aol.com

Abstract—We have previously shown that the regulation by interleukin-1ß (IL-1ß) of inducible nitric oxide synthase (iNOS) involves phospholipase A₂ (PLA₂) metabolites in neonatal ventricular myocytes. Based on studies in which ONO-RS-082 is used to inhibit secretory PLA₂ and methyl arachidonyl fluorophosphonate is used to inhibit cytosolic PLA₂, our data suggest that a secretory PLA₂ metabolite was involved in the regulation by IL-1ß of iNOS. In addition, a third PLA₂ isoform, which is Ca²⁺ independent (iPLA₂), has also been detected in cardiac myocytes and shown to be regulated by cytokines. We tested whether iPLA₂ metabolites are involved in the regulation by IL-1ß of iNOS with the use of bromoenol lactone (BEL), a specific and irreversible inhibitor of iPLA₂. For this, we measured IL-1ß–stimulated nitrite (NOx) production with use of the Griess reagent, prostaglandin E₂ (PGE₂) production with use of an enzyme immunoassay, and arachidonic acid release in the presence and absence of BEL. We also detected iNOS and iPLA₂ proteins by Western blotting. Treatment with IL-1ß (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 PGE₂ production was increased by 300-fold. When neonatal ventricular myocytes were treated with 10 µmol/L BEL, both IL-1ß–stimulated PGE₂ production and arachidonic acid release were inhibited. BEL inhibited IL-1ß–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 iPLA₂ metabolite, perhaps lysophosphatidic acid, may be involved in the IL-1ß–signaling pathway, regulating the synthesis of iNOS.

Key Words: nitric oxide • arachidonic acids • interleukins • myocytes

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