Oxidized low-density lipoprotein increases osteopontin expression by generation of oxidative stress.
Osteopontin (OPN) is an important mediator of inflammation and is involved in the generation of atherosclerotic lesions. Oxidized LDL (OxLDL) increased the intracellular and secreted levels of OPN in rat smooth muscle cells in a dose- and time-dependent manner. Experiments with kinase inhibitors demonstrated that this effect was mediated by ERK and JNK, but not p38. OxLDL induced oxidative stress, measured by the intracellular levels of reactive oxygen species (ROS) and lipid peroxidation products. The increase in OPN levels was reproduced by the lipid extract of the particle and prevented by the antioxidant vitamin E. Furthermore, ROS generated by UVA irradiation or treatment with pro-oxidant compounds such as buthionine sulfoximine or H(2)O(2) also enhanced intracellular and secreted OPN. Finally, OxLDL also augmented OPN levels in other cell types such as fibroblasts, keratinocytes, and endothelial cells. This work demonstrates the role of OxLDL in the expression of the OPN gene and further highlights the role of oxidative stress in the regulation of this cytokine. This might be related to the proinflammatory effects of OxLDL in the initiation and progression of atherosclerotic plaque.
Mazière
Cécile
C
Biochemistry Laboratory, CHU Nord, Amiens F-80000, France. maziere.cecile@chu-amiens.fr
Gomila
Cathy
C
Mazière
Jean-Claude
JC
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D024505:Tocopherols / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D053495:Osteopontin; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D024505:Tocopherols