title: Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis.
  
  
  RESULTS
  To investigate the contribution of macrophage PPARgamma expression on atherogenesis in vivo, we generated macrophage-specific PPARgamma knockout (MacPPARgammaKO) mice. C57BL/6 and low-density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice were reconstituted with MacPPARgammaKO or wild-type marrow and challenged with an atherogenic diet. No differences were found in serum lipids between recipients reconstituted with MacPPARgammaKO and wild-type marrow. In contrast, both C57BL/6 and LDLR(-/-) mice transplanted with MacPPARgammaKO marrow had significantly larger atherosclerotic lesions than control recipients. In addition, MacPPARgammaKO-->LDLR(-/-) mice had higher numbers of macrophages in atherosclerotic lesions compared with controls. Peritoneal macrophages isolated from the MacPPARgammaKO mice had decreased uptake of oxidized but not acetylated LDL and showed no changes in either cholesterol efflux or inflammatory cytokine expression. Macrophages from MacPPARgammaKO mice had increased levels of migration and CC chemokine receptor 2 (CCR2) expression compared with wild-type macrophages.
  
  
  CONCLUSIONS
  Thus, macrophage PPARgamma deficiency increases atherosclerosis under conditions of mild and severe hypercholesterolemia, indicating an antiatherogenic role for PPARgamma, which may be caused, at least in part, by modulation of CCR2 expression and monocyte recruitment.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA. vladimir.babaev@vanderbilt.edu
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ryzhov
authors.forename: Valentina
authors.initials: V
authors.lastname: Kon
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Breyer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D016026:Bone Marrow Transplantation; D008078:Cholesterol, LDL / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression / Q000276:immunology; D006937:Hypercholesterolemia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C515335:Ccr2 protein, mouse; D008078:Cholesterol, LDL; D016207:Cytokines; D047495:PPAR gamma; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011973:Receptors, LDL