Peroxisome Proliferator–Activated Receptor (cid:1) Induces NADPH Oxidase Activity in Macrophages, Leading to the Generation of LDL with PPAR- (cid:1) Activation Properties

—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- (cid:1) , but not PPAR- (cid:2) agonists, increased the production of ROS (H 2 O 2 and O 2 .) in human and murine macrophages. PPAR- (cid:1) 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- (cid:1) agonists tested, but was mediated by PPAR- (cid:1) , because the effects were lost in bone marrow–derived macrophages from PPAR- (cid:1) (cid:1) / (cid:1) mice. The PPAR- (cid:1) –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- (cid:1) agonists increased O 2 . production measured by superoxide dismutase–inhibitable cytochrome c reduction; (3) PPAR- (cid:1) 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 (cid:1) / (cid:1) and gp91 phox (cid:1) / (cid:1) macrophages. Finally, induction of NADPH oxidase by PPAR- (cid:1) agonists resulted in the formation of oxidized LDL metabolites that exert PPAR- (cid:1) –independent proinflammatory and PPAR- (cid:1) –dependent decrease of lipopolysaccharide-induced inducible nitric oxide synthase expression in macrophages. These data identify a novel mechanism of autogeneration of endogenous PPAR- (cid:1) ligands via stimulation of NADPH oxidase activity. ( Circ Res . 2004;95:1174-1182.)

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