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(Hypertension. 1998;31:218.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Phospholipase A₂ Metabolites Regulate Inducible Nitric Oxide Synthase in Myocytes

Margot C. LaPointe; Jodi R. Sitkins

From the Hypertension and Vascular Research Division (M.C.L., J.R.S.), 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 48202-2689. E-mail mclapointe{at}aol.com

The proinflammatory cytokine interleukin-1ß (IL) stimulates inducible nitric oxide synthase (iNOS) mRNA, protein, and nitric oxide (NO) production in neonatal ventricular myocytes (NVM). In other types of cells, IL also activates phospholipase A₂ (PLA₂), which liberates arachidonic acid for the pathways involved in eicosanoid production, and induces the cyclooxygenase-2 (COX-2) isoform, which increases prostanoid production. Since NO has been shown to directly stimulate COX activity and the resulting prostanoids to modulate IL induction of iNOS, we questioned whether PLA₂ and/or COX products are involved in IL regulation of iNOS and NO production in NVM. We first found that IL induced COX-2 mRNA and protein, resulting in 200-fold and 15-fold increases in PGE₂ and 6-keto-PGF₁ (the stable metabolite of PGI₂), respectively. IL-stimulated prostanoid production was inhibited by the COX-2-specific inhibitor NS-398, as well as the nonspecific COX inhibitor indomethacin (INDO). We next studied the involvement of the PLA₂ inhibitor ONO-RS-082 (ONO) and the COX inhibitor INDO in IL regulation of iNOS. Pretreatment with ONO blocked IL-stimulated NO production and iNOS protein, suggesting that PLA₂ products are involved in regulation of iNOS synthesis. Unlike ONO, the COX inhibitor INDO had little effect on IL-stimulated NO. In addition to the COX pathway, arachidonic acid (AA) is also metabolized by the lipoxygenase (LO) pathway. The LO inhibitor nordihydroguaiaretic acid (NDGA) decreased IL-stimulated NO and iNOS synthesis. These data suggest that: (1) IL upregulates COX-2 expression and prostanoid production in NVM; and (2) AA metabolites other than COX products, possibly products of the LO pathway, are involved in IL regulation of iNOS.

Key Words: cardiac myocytes • cyclooxygenase • arachidonic acid • lipoxygenase

Abbreviations: AA = arachidonic acid • BAIC = baicalein • COX = cyclooxygenase • DMEM = Dulbecco’s modified Eagle medium • IL = interleukin-1ß • INDO = indomethacin • iNOS = inducible nitric oxide synthase • JNK = c-Jun kinase • LO = lipoxygenase • LPA = lysophosphatidic acid • LPC = lysophosphatidylcholine • MAFP = methyl arachidonyl fluorophosphonate • MAPK = mitogen-activated protein kinase • NO = nitric oxide • NDGA = nordihydroguaiaretic acid • NOx = nitrite • NS-398 = COX-2 inhibitor • NVM = neonatal ventricular myocytes • PAF = platelet-activating factor • PKC = protein kinase C • PLA₂ = phospholipase A₂

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