Fatty acid transduction of nitric oxide signaling: nitrolinoleic acid mediates protective effects through regulation of the ERK pathway.
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.
Iles
Karen E
KE
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. kiles@uab.edu
Wright
Marcienne M
MM
Cole
Marsha P
MP
Welty
Nathan E
NE
Ware
Lorraine B
LB
Matthay
Michael A
MA
Schopfer
Francisco J
FJ
Baker
Paul R S
PR
Agarwal
Anupam
A
Freeman
Bruce A
BA
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
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