Age-associated aortic stenosis in apolipoprotein E-deficient mice.
OBJECTIVE
The present study was designed to assess aortic valve morphology and function in mice of advanced age. We also evaluated the potential contribution of bone-marrow-derived cells to the pathogenesis of aortic stenosis.


BACKGROUND
Age-associated valvular degeneration is characterized by lipid accumulation, collagen deposition, and calcification containing smooth muscle-like cells and osteoblast-like cells. Cellular and molecular factors that mediate these changes remain unknown.


METHODS
We extensively examined the aortic valves of senile wild-type and apolipoprotein E (ApoE)-/- mice with echocardiography. The aortic valves were analyzed by immunohistochemistry and electron microscopy. The bone marrow of wild-type and ApoE-/- mice was reconstituted with that of green fluorescent protein (GFP) or beta-galactosidase (LacZ) mice, which expressed GFP or LacZ ubiquitously.


RESULTS
Transaortic flow velocity was correlated with age in wild-type and ApoE-/- mice. The aortic valves of old ApoE-/- mice showed sclerosis that resembled the pathology of human aortic stenosis. A significant number of GFP-positive cells (10.7 +/- 4.1%) in the sclerotic valves of ApoE-/- mice expressed alpha-smooth muscle actin, whereas most of the GFP-positive cells were identified as endothelial cells or macrophages in wild-type mice. There were bone-marrow-derived cells that were positive for osteoblast-related proteins near the sites of ectopic calcification. The sclerotic valves displayed frequent apoptotic cell death and chemokine expression.


CONCLUSIONS
Senile ApoE-deficient mice display aortic valve sclerosis that is similar to that observed in humans. The sclerotic valves displayed frequent apoptotic cell death and chemokine expression. Smooth muscle-like cells observed in degenerative valves might derive, at least in part, from bone marrow.
Tanaka
Kimie
K
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Sata
Masataka
M
Fukuda
Daiju
D
Suematsu
Yoshihiro
Y
Motomura
Noboru
N
Takamoto
Shinichi
S
Hirata
Yasunobu
Y
Nagai
Ryozo
R
D000367:Age Factors; D000818:Animals; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism*; D001057:Apolipoproteins E / Q000172:deficiency*; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D001057:Apolipoproteins E; C515255:CXCL12 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse