title: Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells.
abstract: Atherogenic lipoproteins such as oxidized LDL are implicated in the pathogenesis of atherosclerosis and renal disease. Fatty acid hydroperoxides and phospholipids such as linoleyl hydroperoxide (LAox or 13-HPODE) and lysophosphatidylcholine (lyso-PC), abundant components of oxidized LDL, mediate the effects of atherogenic lipids. Oxidized LDL has been shown to induce heme oxygenase-1 (HO-1), a microsomal enzyme that is involved in heme detoxification and is a major endogenous source of carbon monoxide. HO-1 is also induced by many other stimuli that shift cellular redox. To identify the constituents and molecular mechanisms of oxidized LDL-mediated HO-1 induction, human renal epithelial cells and aortic endothelial cells were exposed to LAox and lyso-PC. Exposure to LAox (25 microM) showed an approximately 16-fold induction of HO-1 mRNA, whereas exposure to lyso-PC (25 microM) showed only an approximate 2.6-fold increase. Treatment with actinomycin-D (4 microM), a transcriptional inhibitor, as well as nuclear run-on assays, demonstrated that LAox-mediated HO-1 gene induction is dependent on de novo transcription. Cycloheximide did not affect LAox-mediated HO-1 mRNA induction, suggesting that new protein synthesis is not required for transcriptional induction. Transfection of a human HO-1 promoter-reporter gene construct showed that LAox upregulation of HO-1 occurs via mechanisms different from those of known inducers, heme and cadmium. These studies are the first demonstration that LAox induces HO-1 by transcriptional mechanisms and may have implications in the pathogenesis of cell injury in atherosclerosis and progressive renal disease.
authors.affiliation: Department of Medicine, University of Florida, Gainesville 32610, USA.
authors.forename: A
authors.initials: A
authors.lastname: Agarwal
authors.forename: F
authors.initials: F
authors.lastname: Shiraishi
authors.forename: G A
authors.initials: GA
authors.lastname: Visner
authors.forename: H S
authors.initials: HS
authors.lastname: Nick
mesh_terms: D001011:Aorta / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D008041:Linoleic Acids / Q000235:genetics*; D008054:Lipid Peroxides / Q000235:genetics*; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D008041:Linoleic Acids; D008054:Lipid Peroxides; D008244:Lysophosphatidylcholines; D008565:Membrane Proteins; D012333:RNA, Messenger; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1