Transgenic overexpression of platelet-derived growth factor-C in the mouse heart induces cardiac fibrosis, hypertrophy, and dilated cardiomyopathy
2003 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 163, no 2, 673-682 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2003. Vol. 163, no 2, 673-682 p.
Animals, Biological Markers, Cardiomegaly/*metabolism/pathology/ultrasonography, Cardiomyopathy; Dilated/*metabolism/pathology/ultrasonography, Coronary Vessels/metabolism/pathology, Echocardiography, Female, Fibroblasts/metabolism/pathology, Fibrosis, Gene Expression Regulation, Lymphokines, Male, Mice, Mice; Inbred C57BL, Mice; Transgenic, Myocardium/*metabolism/*pathology, Myocytes; Cardiac/metabolism/pathology, Platelet-Derived Growth Factor/genetics/*metabolism, Promoter Regions (Genetics), Receptor; Platelet-Derived Growth Factor alpha/genetics/metabolism, Up-Regulation
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-10803DOI: 10.1016/S0002-9440(10)63694-2PubMedID: 12875986OAI: oai:DiVA.org:uu-10803DiVA: diva2:38571