Fatty acid transduction of nitric oxide signaling: nitrolinoleic acid potently activates endothelial heme oxygenase 1 expression.
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, LNO(2)) exhibit pluripotent antiinflammatory cell signaling properties. Heme oxygenase 1 (HO-1) is up-regulated as an adaptive response to inflammatory mediators and oxidative stress. LNO(2) (1-10 microM) 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 LNO(2) 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 microM LNO(2) resulted in a 40-fold induction of HO-1 protein that localized to endothelial and smooth muscle cells. Actinomycin D inhibited LNO(2) induction of HO-1 in human aortic endothelial cells, and LNO(2) activated a 4.5-kb human HO-1 promoter construct, indicating transcriptional regulation of the HO-1 gene. The peroxisome proliferator-activated receptor gamma (PPARgamma) receptor antagonist GW9662 did not inhibit LNO(2)-mediated HO-1 induction, and a methyl ester derivative of LNO(2) with diminished PPARgamma binding capability also induced HO-1, affirming a PPARgamma-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 LNO(2), revealing that LNO(2) 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.
Department of Medicine and Anesthesiology, Nephrology Research and Training Center, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Marcienne M
MM
Wright
Francisco J
FJ
Schopfer
Paul R S
PR
Baker
Vijay
V
Vidyasagar
Pam
P
Powell
Phil
P
Chumley
Karen E
KE
Iles
Bruce A
BA
Freeman
Anupam
A
Agarwal
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008041:Linoleic Acids / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds / Q000378:metabolism / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
C501855:10-nitro-9,12-octadecadienoic acid; D005227:Fatty Acids; D008041:Linoleic Acids; D009574:Nitro Compounds; D047495:PPAR gamma; D012333:RNA, Messenger; D009569:Nitric Oxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C491523:Hmox1 protein, rat