Conditional Knockout of Macrophage PPAR Increases Atherosclerosis in C57BL/6 and Low-Density Lipoprotein Receptor–Deficient Mice

Objective—Peroxisome proliferator-activated receptor gamma (PPAR ) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis. Methods and Results—To investigate the contribution of macrophage PPAR expression on atherogenesis in vivo, we generated macrophage-specific PPAR knockout (MacPPAR KO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor–deficient (LDLR / ) mice were reconstituted with MacPPAR KO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPAR KO and wild-type marrow. In contrast, both C57BL/6 and LDLR / mice transplanted with MacPPAR KO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPAR KO3LDLR / mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPAR KO mice had decreased uptake of oxidized but not acetylated LDL and showed no changes in either cholesterol efflux or inflammatory cytokine expression. Macrophages from MacPPAR KO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages. Conclusion—Thus, macrophage PPAR deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPAR , which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment. (Arterioscler Thromb Vasc Biol. 2005;25:1647-1653.)