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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

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

Publication and Content Type

ref (subject category)

art (subject category)