Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10738823 | Free Radical Biology and Medicine | 2005 | 10 Pages |
Abstract
Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNE-mediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription.
Keywords
AP-1EMSASB202190T-TBSPD98059SP600125Heme oxygenase-1HNENFDMStreJnkHRPHO-1ERK4-hydroxynonenalc-Jun N-terminal kinaseEpREMAPKElectrophoretic mobility shift assayOxidative stressFree radicalsMAPK signalingnonfat dry milkstress response elementelectrophile response elementHorseradish peroxidaseactivator protein-1mitogen-activated protein kinaseextracellular signal-regulated kinase
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Authors
Karen E. Iles, Dale A. Dickinson, Amanda F. Wigley, Nathan E. Welty, Volker Blank, Henry Jay Forman,