title: Fatty acid transduction of nitric oxide signaling: nitrolinoleic acid mediates protective effects through regulation of the ERK pathway.
abstract: In vivo and in vitro studies revealed that nitroalkenes serve as protective mediators in the lung by inducing the cytoprotective enzyme heme oxygenase-1 (HO-1). Nitrolinoleic acid (LNO2) increased HO-1 mRNA, protein, and activity in cultured pulmonary epithelial cells treated with 5 to 50 microM LNO2 and in lungs of rats injected intraperitoneally with 2.6 mg/kg LNO2 twice daily for 20 days. Western blotting revealed that HO-1 protein increased significantly within 4 h of in vitro LNO2 addition and was preceded by an increase in HO-1 mRNA, consistent with transcriptional regulation of HO-1 expression by LNO2. LNO2 also dephosphorylated and activated eukaryotic initiation factor 2alpha, a key translational regulatory protein, indicating that increased translation may also contribute to LNO2-induced increases in HO-1. Exposure of cells to LNO2 activated ERK and JNK, as evidenced by increased phosphorylation. Downstream targets of ERK and JNK, Elk-1 and c-Jun, respectively, were also phosphorylated in response to LNO2 exposure. However, inhibitor studies revealed that only the ERK pathway is necessary for the LNO2-mediated increase in HO-1 mRNA and protein. These data reveal that LNO2 induces pulmonary epithelial HO-1 expression and downstream adaptive responses to inflammation via both transcriptional and translational regulatory mechanisms.
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. kiles@uab.edu
authors.forename: Karen E
authors.initials: KE
authors.lastname: Iles
authors.forename: Marcienne M
authors.initials: MM
authors.lastname: Wright
authors.forename: Marsha P
authors.initials: MP
authors.lastname: Cole
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Welty
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Schopfer
authors.forename: Paul R S
authors.initials: PR
authors.lastname: Baker
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008041:Linoleic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D009574:Nitro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation
chemical_list: C501855:10-nitro-9,12-octadecadienoic acid; D015852:Eukaryotic Initiation Factor-2; D005227:Fatty Acids; D008041:Linoleic Acids; D009574:Nitro Compounds; D009569:Nitric Oxide; D051547:Heme Oxygenase-1