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Age-Associated Aortic Stenosis in Apolipoprotein E-Deficient Mice

Kimie Tanaka, MD^_*, Masataka Sata, MD^_*,,,_*, Daiju Fukuda, MD^_*, Yoshihiro Suematsu, MD, Noboru Motomura, MD, Shinichi Takamoto, MD, Yasunobu Hirata, MD^_* and Ryozo Nagai, MD^_*

^_* Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
Department of Cardiothoracic Surgery, University of Tokyo Graduate School of Medicine, Tokyo, Japan
Department of Advanced Clinical Science and Therapeutics, University of Tokyo Graduate School of Medicine, Tokyo, Japan
PRESTO, JST, Kawaguchi, Japan

Manuscript received August 13, 2004; revised manuscript received March 16, 2005, accepted March 22, 2005.

^_* Reprint requests and correspondence: Dr. Masataka Sata, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan (Email: msata-circ{at}umin.ac.jp).

OBJECTIVES: 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.

Abbreviations and Acronyms   ApoE = apolipoprotein E   BMT = bone marrow transplantation   GFP = green fluorescent protein   LacZ = beta-galactosidase   SMA = smooth muscle actin

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