Progressive cardiac fibrosis and myocyte injury in v-fps transgenic mice. A model for primary disorders of connective tissue in the heart?
Transgenic mice that express v-fps protein-tyrosine kinase have severe cardiac or neurologic abnormalities and a high incidence of lymphoid or mesenchymal tumors. The cardiac lesions of v-fps transgenic mice were examined at less than 1, 2, 3, 6, 14, 26, and 43 weeks of age (total N = 19) and compared with nontransgenic littermate controls (N = 34). Three of eight transgenic animals 1 to 4 days old showed moderate proliferation of connective tissue elements most evident along the septal endocardium of the right ventricle. Variable cardiac hypertrophy was seen grossly in 2- to 14-week-old transgenic animals, and marked biventricular dilatation was present in those 6 to 43 weeks of age. Sections of all transgenic mice 3 weeks or older revealed characteristic lesions that consisted of cellular fibrosis in subendocardial, subepicardial, and perivascular sites, with associated proliferation of pericytes and fat cells. Atrophy, degeneration, and loss of entrapped myocytes were noted in transgenic animals as early as 2 weeks of age, but frank coagulative necrosis or myocytolysis was absent at all ages studied. Nonetheless, pleomorphic nuclei were found in occasional myocytes late in disease. Inflammatory cells were rare, as confirmed immunohistochemically (Thy-1 [pan-T], L3T4 [CD4], Lyt-2 [CD8], interleukin-2 receptor [activated lymphocyte], Mac-1 [macrophage], and B220 [pan-B]). Monoclonal immunoreactivity to the v-fps transgene product was positive predominantly in nonmyocyte cardiac constituents. Collectively, the data suggest a primary proliferative abnormality of connective tissue elements in the heart, accompanied by secondary myocyte damage.
Chow
L H
LH
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha.
Yee
S P
SP
Pawson
T
T
McManus
B M
BM
D000375:Aging; D000818:Animals; D003238:Connective Tissue / Q000473:pathology*; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000473:pathology*; D015681:Fusion Proteins, gag-onc / Q000235:genetics*; D006321:Heart / Q000254:growth & development; D006352:Heart Ventricles / Q000473:pathology; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012016:Reference Values
D015681:Fusion Proteins, gag-onc; D011505:Protein-Tyrosine Kinases; C068415:v-fps oncogene protein, Fujinami sarcoma virus