Linoleyl hydroperoxide transcriptionally upregulates heme oxygenase-1 gene expression in human renal epithelial and aortic endothelial cells.
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.
Agarwal
A
A
Department of Medicine, University of Florida, Gainesville 32610, USA.
Shiraishi
F
F
Visner
G A
GA
Nick
H S
HS
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
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