Discovery of an Experimental Model of Unicuspid Aortic Valve.
Discovery of an Experimental Model of Unicuspid Aortic Valve.
复制标题
单瓣主动脉瓣实验模型的发现。
DOI：
10.1161/jaha.117.006908
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发表时间：
2018
影响因子：
5.4
通讯作者：
Heistad,DonaldD
中科院分区：
文献类型：
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作者：
Weiss,RobertM;Chu,Yi;Brooks,RobertM;Lund,DonaldD;Cheng,Justine;Zimmerman,KathyA;Kafa,MelissaK;Sistla,Phanicharan;Doshi,Hardik;Shao,JianQ;ElAccaoui,RamziN;Otto,CatherineM;Heistad,DonaldD
上皮生长因子受体酪氨酸激酶家族调节胚胎半月瓣的形成。我们假设，上皮生长因子受体，这是EgfrVel/+小鼠的显性功能丧失突变的杂合子小鼠，将开发异常主动脉瓣，瓣膜功能障碍，和瓣膜cardiomyosis.Methods and ResultsAortic valves fromEgfrVel/+小鼠和对照小鼠在2.5至4个月的年龄进行了检查，通过光学显微镜。另外，EgfrVel/+和对照小鼠在2.5、4.5、8和12月龄时进行超声心动图检查，随后进行组织学检查。在年轻小鼠中，显微镜显示79%的EgfrVel/+主动脉瓣解剖异常，类似于人类单叶主动脉瓣。在对照小鼠中未观察到异常。12月龄时，EgfrVel/+主动脉瓣的组织结构严重扭曲。超声心动图检测到中度或重度主动脉瓣返流，或主动脉瓣狭窄存在于38%的EgfrVel/+小鼠在2.5月龄（N=24）和74%的8月龄。主动脉瓣功能障碍的EgfrVel/+小鼠出现左心室扩大、肥大和胎儿心肌基因表达程序逆转，但主动脉瓣功能接近正常的EgfrVel/+小鼠则没有。心肌纤维化是最小的或不存在的所有groups.ConclusionsA新的小鼠模型独特地概括了显着的功能，结构和组织学特征的人类单叶主动脉瓣疾病，这是表型不同于其他形式的先天性主动脉瓣疾病。新模型可能有助于阐明先天性异常主动脉瓣变得严重功能障碍的机制。
BackgroundThe epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss‐of‐function mutation in epithelial growth factor receptor, which areEgfrVel/+mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy.Methods and ResultsAortic valves fromEgfrVel/+mice and control mice were examined by light microscopy at 2.5 to 4 months of age. AdditionalEgfrVel/+and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% ofEgfrVel/+aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted inEgfrVel/+aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% ofEgfrVel/+mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred inEgfrVel/+mice with aortic valve dysfunction, but not inEgfrVel/+mice with near‐normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups.ConclusionsA new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.