Urokinase plasminogen activator upregulates paraoxonase 2 expression in macrophages via an NADPH oxidase-dependent mechanism
| Autor: | Orna Nitzan, Rachel Karry, Maayan Shiner, Jasmin Khateeb, Michael Aviram, Nina Volkova, Bianca Fuhrman |
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| Rok vydání: | 2008 |
| Předmět: |
Antioxidant
medicine.medical_treatment Receptors Cell Surface Biology medicine.disease_cause Antioxidants Receptors Urokinase Plasminogen Activator chemistry.chemical_compound Mice Downregulation and upregulation Cell Line Tumor medicine Macrophage Animals Humans RNA Messenger Lythraceae Mice Knockout Oxidase test Mice Inbred BALB C NADPH oxidase Superoxide Aryldialkylphosphatase Plant Extracts Macrophages Acetophenones NADPH Oxidases Atherosclerosis Urokinase-Type Plasminogen Activator Cell biology Urokinase receptor Enzyme Activation Lipoproteins LDL Mice Inbred C57BL Oxidative Stress chemistry Biochemistry Enzyme Induction biology.protein Lipid Peroxidation Cardiology and Cardiovascular Medicine Reactive Oxygen Species Oxidative stress |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 28(7) |
| ISSN: | 1524-4636 |
| Popis: | Objective—Macrophage foam cells are characterized by increased oxidative stress. Macrophage urokinase plasminogen activator (uPA) was shown to contribute to atherosclerosis progression. We hypothesized that uPA atherogenicity is related to its ability to increase macrophage oxidative stress. Increased macrophage oxidative stress in turn was shown to enhance PON2 expression. In the present study we investigated the effect of uPA on macrophage PON2 expression in relation to cellular oxidative stress.Methods and Results—uPA increased PON2 expression in THP-1 macrophages in a dose-dependent manner. This effect required uPA/uPAR interaction and was abolished by cell treatment with antioxidants. uPA increased macrophage oxidative stress, measured by increased lipid peroxides, reactive oxygen species formation, superoxide anion release, and cell-mediated LDL oxidation. These effects were related to uPA-mediated activation of NADPH oxidase, and could not be reproduced in mouse peritoneal macrophages (MPM) harvested from p47phox−/− mice, suggesting a causal relationship between NADPH oxidase activation and the effects of uPA on macrophage oxidative stress and PON2 expression. Finally, MPM from PON2−/−mice were more susceptible to uPA-induced cellular oxidative stress than wild-type MPM, suggesting that PON2 protects against uPA-stimulated macrophage oxidative stress.Conclusions—Upregulation of macrophage PON2 may provide a compensatory protective mechanism against uPA-stimulation of macrophage oxidative stress during atherogenesis. |
| Databáze: | OpenAIRE |
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