title: Pro- and antiatherogenic effects of a dominant-negative P465L mutation of peroxisome proliferator-activated receptor-γ in apolipoprotein E-Null mice.
abstract: OBJECTIVE
  The dominant-negative mutation, P467L, in peroxisome proliferator-activated receptor-γ (PPARγ) affects adipose tissue distribution, insulin sensitivity, and blood pressure in heterozygous humans. We hypothesized that the equivalent mutation, PPARγ-P465L, in mice will worsen atherosclerosis.
  
  
  RESULTS
  Apolipoprotein E-null mice with and without PPARγ-P465L mutation were bred in 129S6 inbred genetic background. Mild hypertension and lipodystrophy of PPARγ-P465L persisted in the apolipoprotein E-null background. Glucose homeostasis was normal, but plasma adiponectin was significantly lower and resistin was higher in PPARγ-P465L mice. Plasma cholesterol and lipoprotein distribution were not different, but plasma triglycerides tended to be reduced. Surprisingly, there were no overall changes in the atherosclerotic plaque size or composition. PPARγ-P465L macrophages had a small decrease in CD36 mRNA and a small yet significant reduction in very-low-density lipoprotein uptake in culture. In unloaded apolipoprotein E-null macrophages with PPARγ-P465L, cholesterol uptake was reduced whereas apolipoprotein AI-mediated efflux was increased. However, when cells were cholesterol loaded in the presence of acetylated low-density lipoprotein, no genotype difference in uptake or efflux was apparent. A reduction of vascular cell adhesion molecule-1 expression in aorta suggests a relatively antiatherogenic vascular environment in mice with PPARγ-P465L.
  
  
  CONCLUSIONS
  Small, competing pro- and antiatherogenic effects of PPARγ-P465L mutation result in unchanged plaque development in apolipoprotein E-deficient mice.
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 710 Brinkhous-Bullitt Bldg, Chapel Hill, NC 27599-7525, USA.
authors.forename: Avani A
authors.initials: AA
authors.lastname: Pendse
authors.forename: Lance A
authors.initials: LA
authors.lastname: Johnson
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Marcus
authors.initials: M
authors.lastname: McNair
authors.forename: C Taylor
authors.initials: CT
authors.lastname: Nipp
authors.forename: Carolyn
authors.initials: C
authors.lastname: Wilhelm
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001786:Blood Glucose / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005838:Genotype; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D052243:Resistin / Q000097:blood; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D001057:Apolipoproteins E; D001786:Blood Glucose; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D047495:PPAR gamma; D052243:Resistin; C499623:Retn protein, mouse; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; C032629:acetyl-LDL; D002784:Cholesterol