Fatty acid transduction of nitric oxide signaling: Nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression

Academic Article

Abstract

  • Nitroalkenes are a class of cell signaling mediators generated by NO and fatty acid-dependent redox reactions. Nitrated fatty acids such as 10- and 12-nitro-9,12-octadecadienoic acid (nitrolinoleic acid, LNO2) exhibit pluripotent antiinflammatory cell signaling properties. Heme oxygenase 1 (HO-1) is up-regulated as an adaptive response to inflammatory mediators and oxidative stress. LNO2 (1-10 μM) induced HO-1 mRNA and protein up to 70- and 15-fold, respectively, in human aortic endothelial cells. This induction of HO-1 occurred within clinical LNO2 concentration ranges, far exceeded responses to equimolar amounts of linoleic acid and oxidized linoleic acid, and rivaled that induced by hemin. Ex vivo incubation of rat aortic segments with 25 μM LNO2 resulted in a 40-fold induction of HO-1 protein that localized to endothelial and smooth muscle cells. Actinomycin D inhibited LNO2 induction of HO-1 in human aortic endothelial cells, and LNO2 activated a 4.5-kb human HO-1 promoter construct, indicating transcriptional regulation of the HO-1 gene. The peroxisome proliferator- activated receptor γ (PPARγ) receptor antagonist GW9662 did not inhibit LNO2-mediated HO-1 induction, and a methyl ester derivative of LNO2 with diminished PPARγ binding capability also induced HO-1, affirming a PPARγ-independent mechanism. The NO scavengers 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and oxymyoglobin partially reversed induction of HO-1 by LNO2, revealing that LNO2 regulates HO-1 expression by predominantly NO-independent mechanisms. In summary, the metabolic and inflammatory signaling actions of nitroalkenes can be transduced by robust HO-1 induction. © 2006 by The National Academy of Sciences of the USA.
  • Digital Object Identifier (doi)

    Author List

  • Wright MM; Schopfer FJ; Baker PRS; Vidyasagar V; Powell P; Chumley P; Iles KE; Freeman BA; Agarwal A
  • Start Page

  • 4299
  • End Page

  • 4304
  • Volume

  • 103
  • Issue

  • 11