Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice.
Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice.
复制标题
瞬态缺口激活诱导长期基因表达变化，导致小鼠病态的窦综合征。
DOI：
10.1161/circresaha.116.310396
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发表时间：
2017-08-18
影响因子：
20.1
通讯作者：
Rentschler S
中科院分区：
文献类型：
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作者：
Qiao Y;Lipovsky C;Hicks S;Bhatnagar S;Li G;Khandekar A;Guzy R;Woo KV;Nichols CG;Efimov IR;Rentschler S
Notch信号在发育期间编程心脏传导，并且在成人心室中，损伤诱导的Notch再激活启动全局转录和表观遗传变化。探讨Notch再激活是否能稳定改变心房肌离子通道基因表达及诱发心律失常。为了模拟损伤反应并确定Notch信号对心房电生理的影响，我们使用多西环素诱导的遗传系统（iNICD）瞬时激活成年心肌内的Notch信号。与对照组相比，在iNICD小鼠中观察到显著的心率减慢和频繁的窦性停顿。iNICD小鼠具有结构正常的心房和保留的窦房结结构，但窦房结和心房传导的关键转录调节因子（包括Nkx 2 -5、Tbx 3和Tbx 5）的表达失调。为了确定诱导的电变化是否稳定，我们短暂激活Notch，然后延长洗脱期，并观察到，除了心率降低外，心房传导速度持续低于对照组。与传导减慢一致，编码心房传导速度的分子决定因素的基因，包括Scn 5a（Nav1.5）和Gja 5（连接蛋白40），在短暂Notch脉冲后持续下调很长时间。与Scn 5a转录物的减少一致，Notch诱导心房动作电位的整体变化，包括降低的dVm/dtmax。此外，小鼠肺静脉附近的程控电刺激表明，在Notch被短暂激活的小鼠中，对房性心律失常的易感性增加。总之，这些结果表明，短暂的Notch激活持续改变离子通道基因表达和心房电生理学，并倾向于一个致心律失常的底物。我们的数据提供了证据，Notch信号调节转录因子和离子通道基因表达在成人心房肌。Notch再激活诱导电变化，导致窦性心动过缓、窦性停搏和房性心律失常的易感性，这导致类似病窦综合征的表型。
Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes. To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility. To model an injury response and determine the effects of Notch signaling on atrial electrophysiology, we transiently activate Notch signaling within adult myocardium using a doxycycline-inducible genetic system (iNICD). Significant heart rate slowing and frequent sinus pauses are observed in iNICD mice when compared with controls. iNICD mice have structurally normal atria and preserved sinus node architecture, but expression of key transcriptional regulators of sinus node and atrial conduction, including Nkx2-5, Tbx3 and Tbx5 are dysregulated. To determine whether the induced electrical changes are stable, we transiently activated Notch followed by a prolonged washout period and observed that, in addition to decreased heart rate, atrial conduction velocity is persistently slower than control. Consistent with conduction slowing, genes encoding molecular determinants of atrial conduction velocity, including Scn5a (Nav1.5) and Gja5 (connexin 40), are persistently down-regulated long after a transient Notch pulse. Consistent with the reduction in Scn5a transcript, Notch induces global changes in the atrial action potential, including a reduced dVm/dtmax. In addition, programmed electrical stimulation near the murine pulmonary vein demonstrates increased susceptibility to atrial arrhythmias in mice where Notch has been transiently activated. Taken together, these results suggest that transient Notch activation persistently alters ion channel gene expression and atrial electrophysiology, and predisposes to an arrhythmogenic substrate. Our data provide evidence that Notch signaling regulates transcription factor and ion channel gene expression within adult atrial myocardium. Notch reactivation induces electrical changes resulting in sinus bradycardia, sinus pauses and a susceptibility to atrial arrhythmias, which contribute to a phenotype resembling sick sinus syndrome.