Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 46, Issue 7, Pages 866-875Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.12.001
Keywords
Nitrated fatty acids; Mitogen activated protein kinases (MAPK); Heme oxygenase-1 (HO-1); Electrophilic lipids; Pulmonary epithelial cells
Funding
- National Institutes of Health [HL58115, HL64937, HL077100, HL68157, HL081332, AHA 0665418U, ADA 7-06-JF-06]
- AHA South-East Affiliate
- Parker B. Francis Fellowship in Pulmonary Research
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fit 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 mu M 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 2 alpha, 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. (C) 2008 Elsevier Inc. All rights reserved.
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