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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
Author(s) -
Kis Adrienn,
Murdoch Colin,
Zhang Min,
Siva Anjana,
RodriguezCuenca Sergio,
Carobbio Stefania,
Lukasik Agnes,
Blount Margaret,
O'Rahilly Steve,
Gray Sarah L.,
Shah Ajay M.,
VidalPuig Antonio
Publication year - 2009
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1093/eurjhf/hfp048
Subject(s) - medicine , endocrinology , cardiac fibrosis , fibrosis , angiotensin ii , cardiac function curve , peroxisome proliferator activated receptor , heart failure , blood pressure , insulin resistance , receptor , diabetes mellitus
Aims Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPARγ) 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 PPARγ may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPARγ causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPARγ 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 PPARγ (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 PPARγ and AngII‐induced hypertension and suggest that patients with PPARγ mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis.