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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1361.)
© 2008 American Heart Association, Inc.

Cell Biology and Signaling

Urokinase Plasminogen Activator Upregulates Paraoxonase 2 Expression in Macrophages Via an NADPH Oxidase-Dependent Mechanism

Bianca Fuhrman; Jasmin Khateeb; Maayan Shiner; Orna Nitzan; Rachel Karry; Nina Volkova; Michael Aviram

From the Lipid Research Laboratory (B.F., J.K., M.S., R.K., N.V., M.A.), Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, and Rambam Medical Center, Haifa; and Internal Medicine Ward C (O.N.), Haemek Medical Center, Afula, Israel.

Correspondence to Bianca Fuhrman, DSc, Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel, 31096. E-mail Fuhrman{at}tx.technion.ac.il

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 p47^phox–/– 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.

Our results demonstrate that uPA upregulates macrophage PON2 expression, secondary to NADPH oxidase activation. Macrophage PON2 upregulation may provide a compensatory protective mechanism against uPA-induced NADPH oxidase-dependent stimulation of macrophage oxidative stress during atherogenesis.

Key Words: urokinase • paraoxonase 2 (PON2) • macrophages • NADPH oxidase • antioxidants

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