Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

Adrienn Kis, Colin Murdoch, Min Zhang, Anjana Siva, Sergio Rodriguez-Cuenca, Stefania Carobbio, Agnes Lukasik, Margaret Blount, Steve O'Rahilly, Sarah L. Gray, Ajay M. Shah, Antonio Vidal-Puig

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Abstract

Aims: Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPAR?) 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 PPAR? may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPAR? causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPAR? function on the development of cardiac fibrosis and hypertrophy in a murine model carrying a human dominant-negative mutation in PPARγ.

Methods and results
: Mice with a dominant-negative point mutation in PPAR? (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.
Conclusion: These results show synergistic pathogenic effects between the presence of defective PPAR? and AngII-induced hypertension and suggest that patients with PPAR? mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis.
Original languageEnglish
Pages (from-to)533-541
Number of pages9
JournalEuropean Journal of Heart Failure
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 2009

Keywords

  • hypertension
  • left ventricular hypertrophy
  • interstitial fibrosis
  • dominant-negative PPARγ
  • lipodystrophy

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    Kis, A., Murdoch, C., Zhang, M., Siva, A., Rodriguez-Cuenca, S., Carobbio, S., Lukasik, A., Blount, M., O'Rahilly, S., Gray, S. L., Shah, A. M., & Vidal-Puig, A. (2009). Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice. European Journal of Heart Failure, 11(6), 533-541. https://doi.org/10.1093/eurjhf/hfp048