Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice.
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.
Babaev
Vladimir R
VR
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA. vladimir.babaev@vanderbilt.edu
Yancey
Patricia G
PG
Ryzhov
Sergey V
SV
Kon
Valentina
V
Breyer
Matthew D
MD
Magnuson
Mark A
MA
Fazio
Sergio
S
Linton
MacRae F
MF
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
C515335:Ccr2 protein, mouse; D008078:Cholesterol, LDL; D016207:Cytokines; D047495:PPAR gamma; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011973:Receptors, LDL