Transgenic overexpression of platelet-derived growth factor-C in the mouse heart induces cardiac fibrosis, hypertrophy, and dilated cardiomyopathy.
The platelet-derived growth factors are implicated in development of fibrotic reactions and disease in several organs. We have overexpressed platelet-derived growth factor-C in the heart using the alpha-myosin heavy chain promoter and created a transgenic mouse that exhibits cardiac fibrosis followed by hypertrophy with sex-dependent phenotypes. The transgenic mice developed several pathological changes including cardiac fibroblast proliferation and deposition of collagen, hypertrophy, vascular defects, and the presence of Anitschkow cells in the adult myocardium. Male mice developed a hypertrophic phenotype, whereas female mice were more severely affected and developed dilated cardiomyopathy, leading to heart failure and sudden death. The vascular defects initially included dilation of microvessels and vascular leakage. Subsequently, a marked loss of microvessels, formation of large vascular sac-like structures, and an increased density of smooth muscle-coated vessels were observed in the myocardium. In part, the observed vascular changes may be because of an up-regulation of vascular endothelial growth factor in cardiac fibroblasts of the transgenic hearts. This unique animal model reveals that a potent mitogen for cardiac fibroblasts result in an expansion of the interstitium that induce a secondary sex-dependent hypertrophic response in the cardiomyocytes.
Pontén
Annica
A
Ludwig Institute for Cancer Research, Stockholm Branch, Stockholm, Sweden.
Li
Xuri
X
Thorén
Peter
P
Aase
Karin
K
Sjöblom
Tobias
T
Ostman
Arne
A
Eriksson
Ulf
U
D000818:Animals; D015415:Biomarkers; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004452:Echocardiography; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D008222:Lymphokines; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D015415:Biomarkers; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D020796:Receptor, Platelet-Derived Growth Factor alpha