Age-Associated Aortic Stenosis in Apolipoprotein E-Deficient Mice

Abstract

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. 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. 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. 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. 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.