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(Circulation Research. 2004;95:1174.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Peroxisome Proliferator–Activated Receptor Induces NADPH Oxidase Activity in Macrophages, Leading to the Generation of LDL with PPAR- Activation Properties

Elisabeth Teissier, Atsushi Nohara, Giulia Chinetti, Réjane Paumelle, Bertrand Cariou, Jean-Charles Fruchart, Ralf P. Brandes, Ajay Shah, Bart Staels

From the UR 545 INSERM-Institut Pasteur de Lille and Faculté de Pharmacie (E.T., A.N., G.C., R.P., B.C., J.-C.F., B.S.), Université de Lille II, Lille, France; Klinikum Goethe-Universität (R.B.), Frankfurt-am-Main, Germany; and the Department of Cardiology (A.S.), GKT School of Medicine, King’s College, London, UK.

Correspondence to Bart Staels, UR545 INSERM, Département d’Athérosclérose, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP245, Lille 59019, France. E-mail Bart.Staels{at}pasteur-lille.fr

Peroxisome proliferator–activated receptors (PPARs) are nuclear receptors controlling lipid and glucose metabolism as well as inflammation. PPARs are expressed in macrophages, cells that also generate reactive oxygen species (ROS). In this study, we investigated whether PPARs regulate ROS production in macrophages. Different PPAR-, but not PPAR- agonists, increased the production of ROS (H₂O₂ and ) in human and murine macrophages. PPAR- activation did not induce cellular toxicity, but significantly decreased intracellular glutathione levels. The increase in ROS production was not attributable to inherent prooxidant effects of the PPAR- agonists tested, but was mediated by PPAR-, because the effects were lost in bone marrow–derived macrophages from PPAR-^–/– mice. The PPAR-–induced increase in ROS was attributable to the induction of NADPH oxidase, because (1) preincubation with the NADPH oxidase inhibitor diphenyleneiodinium prevented the increase in ROS production; (2) PPAR- agonists increased production measured by superoxide dismutase–inhibitable cytochrome c reduction; (3) PPAR- agonists induced mRNA levels of the NADPH oxidase subunits p47^phox, p67^phox, and gp91^phox and membrane p47^phox protein levels; and (4) induction of ROS production was abolished in p47^phox–/– and gp91^phox–/– macrophages. Finally, induction of NADPH oxidase by PPAR- agonists resulted in the formation of oxidized LDL metabolites that exert PPAR-–independent proinflammatory and PPAR-–dependent decrease of lipopolysaccharide-induced inducible nitric oxide synthase expression in macrophages. These data identify a novel mechanism of autogeneration of endogenous PPAR- ligands via stimulation of NADPH oxidase activity.

Key Words: macrophages • nuclear receptors • NADPH oxidase • reactive oxygen species • inflammation

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