Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction
Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction
复制标题
DOI：
10.1161/01.res.0000141136.85194.f0
复制
发表时间：
2004-09-03
影响因子：
20.1
通讯作者：
Johnson, RL
中科院分区：
文献类型：
--
作者：
Kokubo, H;Miyagawa-Tomita, S;Johnson, RL
Notch信号通路中涉及的基因已被证明是心血管发育的关键调节因子。体外研究表明，Notch信号通路直接调控Hesr基因的转录，编码碱性螺旋-环-螺旋转录因子。为了评估Hesr基因在心血管发育中的功能作用，我们培育了Hesr2基因定向中断的小鼠，并使用超声心动图分析了突变小鼠的心功能。在出生后早期，大多数Hesr2纯合子小鼠死于充血性心力衰竭伴明显的心脏增大。出生5天的纯合子小鼠的经胸超声心动图显示三尖瓣和二尖瓣反流，左室腔扩张，左室短轴缩短率明显减小。血流动力学异常伴有形态改变，如房室瓣发育不良、膜周室间隔缺损和继发孔型房间隔缺损。在HES2纯合子小鼠中，房室瓣反流可归因于房室瓣发育不良，这很可能是导致心脏功能障碍的原因。这些观察结果表明，Notch信号靶标HESR2在房室瓣膜的形成和功能中起着重要作用。此外，Hesr2的活性可能对心肌细胞的正常发育很重要，从而确保正常的左心室收缩能力。由于Hesr2基因缺失小鼠表达的心脏异常的独特光谱，它们代表了一个有用的模型系统，用于阐明心脏功能障碍的遗传基础。
Genes involved in the Notch signaling pathway have been shown to be critical regulators of cardiovascular development. In vitro studies have revealed that the Notch signaling pathway directly regulates transcription of hairy and enhancer of split-related (hesr) genes, encoding basic helix-loop-helix transcription factors. To assess the functional role of hesr genes in cardiovascular development, we generated mice with a targeted disruption of the hesr2 gene and used echocardiography to analyze heart function of the mutant mice. In the early postnatal period, a majority of hesr2 homozygous mice die as a result of congestive heart failure accompanied by pronounced heart enlargement. Transthoracic echocardiography on 5-day-old homozygous mice revealed tricuspid and mitral valve regurgitation and a dilated left ventricular chamber with markedly diminished fractional shortening of the left ventricle. The hemodynamic anomalies were accompanied by morphological changes, such as dysplastic atrioventricular (AV) valves, a perimembranous ventricular septal defect, and a secundum atrial septal defect. AV valve regurgitations attributable to dysplasia of the AV valves were most likely responsible for the heart dysfunction in hesr2 homozygous mice. These observations indicate that the Notch signaling target hesr2 plays an important role in the formation and function of the AV valves. In addition, hesr2 activity may be important for proper development of cardiomyocytes, thereby assuring normal left ventricular contractility. Because of the unique spectrum of cardiac anomalies expressed by hesr2-null mice, they represent a useful model system for elucidating the genetic basis of heart dysfunction.