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European Journal of Heart Failure Advance Access originally published online on April 24, 2009
European Journal of Heart Failure 2009 11(6):533-541; doi:10.1093/eurjhf/hfp048
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.
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Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

Adrienn Kis1,{dagger}, Colin Murdoch2,{dagger}, Min Zhang2, Anjana Siva2, Sergio Rodriguez-Cuenca1, Stefania Carobbio1, Agnes Lukasik1, Margaret Blount1, Steve O'Rahilly1, Sarah L. Gray3, Ajay M. Shah2,* and Antonio Vidal-Puig1,*

1 Metabolic Research Laboratories, Level 4, Institute of Metabolic Sciences, Box 289, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
2 Cardiovascular Division, King’s College London British Heart Foundation Centre of Research Excellence, 125 Coldharbour Lane, London SE5 9NU, UK
3 Northern Medical Program, University of Northern British Columbia, 3333 University Way, Prince George BC, Prince George BC V2N 479, Canada

* Corresponding author. Tel: +44 1223 762790, Email: ajv22{at}medschl.cam.ac.uk (A.V.-P.) and Tel: +44 20 7848 5189, Fax: +44 20 7848 5193, Email: ajay.shah{at}kcl.ac.uk (A.M.S.)


  Abstract

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

Methods and results: Mice with a dominant-negative point mutation in PPAR{gamma} (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{gamma} and AngII-induced hypertension and suggest that patients with PPAR{gamma} mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis.

Key Words: Hypertension • Left ventricular hypertrophy • Interstitial fibrosis • Dominant-negative PPAR{gamma} • Lipodystrophy

Received September 9, 2008; Revised February 12, 2009; Accepted February 26, 2009

{dagger} The first two authors contributed equally to the study.


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