Conditional knockout of macrophage PPARγ increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice

Objective-Peroxisome proliferator-activated receptor gamma (PPAR gamma) 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 gamma expression on atherogenesis in vivo, we generated macrophage-specific PPAR gamma knockout (MacPPAR gamma KO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor-deficient (LDLR-/-) mice were reconstituted with MacPPAR gamma KO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPAR gamma KO and wild-type marrow. In contrast, both C57BL/6 and LDLR-/- mice transplanted with MacPPAR gamma KO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPAR gamma KO -> LDLR-/- mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPAR gamma 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 gamma KO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages. Conclusion-Thus, macrophage PPAR gamma deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPAR gamma, which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment.