Age-associated aortic stenosis in apolipoprotein E-deficient mice.
Age-associated aortic stenosis in apolipoprotein E-deficient mice.
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DOI：
10.1016/j.jacc.2005.03.058
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发表时间：
2005-07
影响因子：
24
通讯作者：
Kimie Tanaka;M. Sata;D. Fukuda;Y. Suematsu;N. Motomura;S. Takamoto;Y. Hirata;R. Nagai
中科院分区：
文献类型：
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作者：
Kimie Tanaka;M. Sata;D. Fukuda;Y. Suematsu;N. Motomura;S. Takamoto;Y. Hirata;R. Nagai
目的本研究旨在评估高龄小鼠的主动脉瓣形态和功能。我们还评估了骨髓源性细胞对主动脉瓣狭窄发病机制的潜在贡献。背景年龄相关的瓣膜变性的特征是脂质积累、胶原沉积以及含有平滑肌样细胞和成骨细胞样细胞的钙化。介导这些变化的细胞和分子因素仍然未知。 方法我们通过超声心动图广泛检查了老年野生型和载脂蛋白 E (ApoE)−/− 小鼠的主动脉瓣。通过免疫组织化学和电子显微镜分析主动脉瓣。用绿色荧光蛋白（GFP）或β-半乳糖苷酶（LacZ）小鼠的骨髓重建野生型和ApoE−/−小鼠的骨髓，这些小鼠普遍表达GFP或LacZ。结果跨主动脉流速与野生型和ApoE−/−小鼠的年龄相关。老 ApoE−/− 小鼠的主动脉瓣显示出类似于人类主动脉狭窄病理的硬化。 ApoE−/− 小鼠的硬化瓣膜中大量 GFP 阳性细胞 (10.7 ± 4.1%) 表达 α-平滑肌肌动蛋白，而野生型小鼠中的大多数 GFP 阳性细胞被鉴定为内皮细胞或巨噬细胞。在异位钙化部位附近存在成骨细胞相关蛋白呈阳性的骨髓来源细胞。硬化瓣膜表现出频繁的细胞凋亡和趋化因子表达。结论老年ApoE缺陷小鼠表现出与人类观察到的相似的主动脉瓣硬化。硬化瓣膜表现出频繁的凋亡细胞死亡和趋化因子表达。在退行性瓣膜中观察到的平滑肌样细胞可能至少部分源自骨髓。
ObjectivesThe 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.BackgroundAge-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.MethodsWe 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.ResultsTransaortic 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.ConclusionsSenile 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.