Severe deficiency of coagulation Factor VII results in spontaneous cardiac fibrosis in mice.
Mice genetically modified to produce low levels (approximately 1% of wild-type) of coagulation FVII presented with echocardiographic evidence of heart abnormalities. Decreases in ventricular size and reductions in systolic and diastolic functions were found, suggestive of a restrictive cardiomyopathy and consistent with an infiltrative myopathic process. Microscopic analysis of mouse hearts showed severe patchy fibrosis in the low-FVII mice. Haemosiderin deposition was discovered in hearts of these mice, along with increases in inflammatory cell number, ultimately resulting in widespread collagen deposition. Significant increases in mRNA levels of TGFbeta, TNFalpha and several matrix metalloproteinases in low-FVII mice, beginning at early ages, supported a state of cardiac remodelling associated with the fibrotic pathology. Mechanistic time-course studies suggested that cardiac fibrosis in low-FVII mice originated from bleeding in heart tissue, resulting in the recruitment of leukocytes, which released inflammatory mediators and induced collagen synthesis and secretion. These events led to necrosis of cardiomyocytes and collagen deposition, characteristics of cardiac fibrosis. The results of this study demonstrated that haemorrhagic and inflammatory responses to a severe FVII deficiency resulted in the development of cardiac fibrosis, observed echocardiographically as a restrictive cardiomyopathy, with compromised ventricular diastolic and systolic functions.
Xu
H
H
W. M. Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Noria
F
F
Sandoval-Cooper
M J
MJ
Menchen
H
H
Donahue
D L
DL
Ploplis
V A
VA
Castellino
F J
FJ
D000818:Animals; D003094:Collagen / Q000032:analysis; D015150:Echocardiography, Doppler; D005168:Factor VII Deficiency / Q000473:pathology*; D005355:Fibrosis; D006331:Heart Diseases / Q000473:pathology; D006470:Hemorrhage / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009206:Myocardium / Q000737:chemistry / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D003094:Collagen