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

Fingerprint

Fibrosis
Hypertension
Mutation
Angiotensin II
Cardiomegaly
Blood Pressure
Lipodystrophy
Peroxisome Proliferator-Activated Receptors
Dyslipidemias
Point Mutation
Insulin Resistance
Body Weight
Pharmacology
Gene Expression
Weights and Measures
Mortality
Therapeutics

Keywords

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

Cite this

Kis, Adrienn ; Murdoch, Colin ; Zhang, Min ; Siva, Anjana ; Rodriguez-Cuenca, Sergio ; Carobbio, Stefania ; Lukasik, Agnes ; Blount, Margaret ; O'Rahilly, Steve ; Gray, Sarah L. ; Shah, Ajay M. ; Vidal-Puig, Antonio. / Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice. In: European Journal of Heart Failure. 2009 ; Vol. 11, No. 6. pp. 533-541.
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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.",
keywords = "hypertension, left ventricular hypertrophy, interstitial fibrosis, dominant-negative PPARγ, lipodystrophy",
author = "Adrienn Kis and Colin Murdoch and Min Zhang and Anjana Siva and Sergio Rodriguez-Cuenca and Stefania Carobbio and Agnes Lukasik and Margaret Blount and Steve O'Rahilly and Gray, {Sarah L.} and Shah, {Ajay M.} and Antonio Vidal-Puig",
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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, SL, Shah, AM & 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, vol. 11, no. 6, pp. 533-541. https://doi.org/10.1093/eurjhf/hfp048

Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice. / Kis, Adrienn; Murdoch, Colin; Zhang, Min; Siva, Anjana; Rodriguez-Cuenca, Sergio; Carobbio, Stefania; Lukasik, Agnes; Blount, Margaret; O'Rahilly, Steve; Gray, Sarah L.; Shah, Ajay M.; Vidal-Puig, Antonio.

In: European Journal of Heart Failure, Vol. 11, No. 6, 06.2009, p. 533-541.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

AU - Kis, Adrienn

AU - Murdoch, Colin

AU - Zhang, Min

AU - Siva, Anjana

AU - Rodriguez-Cuenca, Sergio

AU - Carobbio, Stefania

AU - Lukasik, Agnes

AU - Blount, Margaret

AU - O'Rahilly, Steve

AU - Gray, Sarah L.

AU - Shah, Ajay M.

AU - Vidal-Puig, Antonio

PY - 2009/6

Y1 - 2009/6

N2 - 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.

AB - 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.

KW - hypertension

KW - left ventricular hypertrophy

KW - interstitial fibrosis

KW - dominant-negative PPARγ

KW - lipodystrophy

U2 - 10.1093/eurjhf/hfp048

DO - 10.1093/eurjhf/hfp048

M3 - Article

VL - 11

SP - 533

EP - 541

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

SN - 1388-9842

IS - 6

ER -