title: Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice.
abstract: OBJECTIVE
  Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPARgamma) typically develop a complex metabolic syndrome characterized by insulin resistance, diabetes, lipodystrophy, hypertension, and dyslipidaemia which is likely to increase their cardiovascular risk. Despite evidence that the activation of PPARgamma may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPARgamma causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPARgamma function on the development of cardiac fibrosis and hypertrophy in a murine model carrying a human dominant-negative mutation in PPARgamma.
  
  
  RESULTS
  Mice with a dominant-negative point mutation in PPARgamma (P465L) and their wild-type (WT) littermates were treated with either subcutaneous angiotensin II (AngII) infusion or saline for 2 weeks. Heterozygous P465L and WT mice developed a similar increase in systolic blood pressure, but the mutant mice developed significantly more severe cardiac fibrosis to AngII that correlated with increased expression of profibrotic genes. Both groups similarly increased the heart weight to body weight ratio compared with saline-treated controls. There were no differences in fibrosis between saline-treated WT and P465L mice.
  
  
  CONCLUSIONS
  These results show synergistic pathogenic effects between the presence of defective PPARgamma and AngII-induced hypertension and suggest that patients with PPARgamma mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis.
authors.affiliation: Metabolic Research Laboratories, Institute of Metabolic Sciences, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kis
authors.forename: Colin
authors.initials: C
authors.lastname: Murdoch
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Anjana
authors.initials: A
authors.lastname: Siva
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodriguez-Cuenca
authors.forename: Stefania
authors.initials: S
authors.lastname: Carobbio
authors.forename: Agnes
authors.initials: A
authors.lastname: Lukasik
authors.forename: Margaret
authors.initials: M
authors.lastname: Blount
authors.forename: Steve
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
mesh_terms: D000483:Alleles; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*
chemical_list: D047495:PPAR gamma; D012313:RNA; D019255:NADPH Oxidases