Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL
Diet-Induced Aortic Valve Disease in Mice Haploinsufficient for the Notch Pathway Effector RBPJK/CSL
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DOI：
10.1161/atvbaha.111.227561
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发表时间：
2011-07-01
影响因子：
8.7
通讯作者：
Luis de la Pompa, Jose
中科院分区：
文献类型：
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作者：
Nus, Meritxell;MacGrogan, Donal;Luis de la Pompa, Jose
钙化性主动脉瓣疾病与动脉粥样硬化相似，这两种疾病都是由慢性炎症和内皮功能障碍引起的。杂合子NOTCH1突变与钙化性主动脉疾病和二叶主动脉瓣相关。我们研究了Notch信号通路基因失活的小鼠在暴露于易患饮食时是否容易发生瓣膜疾病。方法和结果-使用多普勒超声心动图、组织学、免疫组织化学、定量基因表达分析和细胞培养测定，我们研究了补充维生素D的高胆固醇饮食对Notch1受体或效应子无效突变杂合子小鼠的影响，转录因子基因RBPJk。高脂饮食16周后，在杂合子RBPJk小鼠中检测到钙化性主动脉疾病。瓣叶分析显示巨噬细胞浸润、胶原沉积增强、前骨生成蛋白表达和钙化。Notch1基因敲除杂合子小鼠的组织病理学变化较轻，未出现任何显著的血流动力学紊乱。瓣膜疾病与喂养高脂饮食的RBPJk杂合小鼠瓣膜中Notch靶基因Hey1表达减少相关。与体内数据一致，Notch信号抑制猪瓣膜间质细胞导致下调HEY1转录，激活成骨标记物，并增加钙化结节formation.Conclusion-We表明，Notch信号中断通过RBPJk杂合失活的结果在主动脉瓣疾病。Notch 1杂合小鼠未表现出功能障碍，这表明额外的Notch受体可能参与主动脉瓣稳态和疾病。我们的数据建立了钙化性主动脉瓣疾病的遗传小鼠模型，并可能有助于识别瓣膜NOTCH信号减少的患者人群，这些患者具有发生这种疾病的风险。（Arterioscler Thromb Vasc Biol.2011; 31：1580 - 1588.）
Objective-Calcific aortic valve disease is similar to atherosclerosis in that both diseases result from chronic inflammation and endothelial dysfunction. Heterozygous NOTCH1 mutations have been associated to calcific aortic disease and a bicuspid aortic valve. We investigated whether mice with genetic inactivation of the Notch signaling pathway are prone to develop valve disease when exposed to a predisposing diet.Methods and Results-Using Doppler echocardiography, histology, immunohistochemistry, quantitative gene expression analysis, and cell culture assays, we examined the effect of a hypercholesterolemic diet supplemented with vitamin D on mice heterozygous for null mutations in the Notch1 receptor or the effector transcription factor gene RBPJk. After 16 weeks on the hyperlipidemic diet, calcific aortic disease was detected in heterozygous RBPJk mice. Analysis of valve leaflets revealed macrophage infiltration, enhanced collagen deposition, proosteogenic protein expression, and calcification. Heterozygous null Notch1 mice displayed milder histopathologic changes and did not develop any significant hemodynamic disturbance. Valvular disease correlated with reduced expression of the Notch target gene Hey1 in valves of RBPJk heterozygous mice fed the hyperlipidemic diet. Consistent with the in vivo data, Notch signaling inhibition in porcine valve interstitial cells led to downregulation of HEY1 transcription, activation of osteogenic markers, and increased calcified nodule formation.Conclusion-We show that Notch signaling disruption via RBPJk heterozygous inactivation results in aortic valve disease. Notch1 heterozygous mice do not show functional impairment, suggesting that additional Notch receptors may be involved in aortic valve homeostasis and disease. Our data establish a genetic mouse model of calcific aortic valve disease and may help to identify a patient population with reduced valvular NOTCH signaling at risk for developing this disease. (Arterioscler Thromb Vasc Biol. 2011; 31: 1580-1588.)