当前位置: X-MOL 学术Circ. Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice.
Circulation Research ( IF 16.5 ) Pub Date : 2017-08-18 , DOI: 10.1161/circresaha.116.310396
Yun Qiao 1 , Catherine Lipovsky 1 , Stephanie Hicks 1 , Somya Bhatnagar 1 , Gang Li 1 , Aditi Khandekar 1 , Robert Guzy 1 , Kel Vin Woo 1 , Colin G Nichols 1 , Igor R Efimov 1 , Stacey Rentschler 1
Affiliation  

Rationale: Notch signaling programs cardiac conduction during development, and in the adult ventricle, injury-induced Notch reactivation initiates global transcriptional and epigenetic changes.
Objective: To determine whether Notch reactivation may stably alter atrial ion channel gene expression and arrhythmia inducibility.
Methods and Results: 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 (inducible Notch intracellular domain [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 (NK2 homeobox 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 downregulated 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.
Conclusions: 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.


中文翻译:

瞬时刻槽激活诱导长期基因表达变化,导致小鼠病态窦房结综合征。

原理: Notch信号传导可在发育过程中控制心脏传导,在成年心室中,损伤诱导的Notch激活可引发整体转录和表观遗传学变化。
目的:确定Notch的激活是否可以稳定改变心房离子通道基因的表达和心律失常的诱导性。
方法和结果:为了模拟损伤反应并确定Notch信号对心房电生理的影响,我们使用强力霉素诱导的遗传系统(诱导型Notch细胞内结构域[iNICD])短暂激活了成人心肌内的Notch信号。与对照组相比,在iNICD小鼠中观察到明显的心率减慢和频繁的窦性停顿。iNICD小鼠具有正常的心房结构并保留了窦房结结构,但是窦房结和心房传导的关键转录调节因子的表达包括Nkx2-5(NK2同源框5), Tbx3Tbx5失调。为了确定感应的电变化是否稳定,我们短暂激活Notch,然后延长冲洗时间,观察到,除了心率降低之外,心房传导速度持续比对照慢。与传导减慢相一致,在短暂的Notch脉冲后很长时间,编码心房传导速度分子决定因子(包括Scn5aNav1.5)和Gja5(连接蛋白40))的基因持续下调。与Scn5a转录物的减少一致,Notch诱导了心房动作电位的整体变化,包括dV m / dt max的减少。。此外,在鼠肺静脉附近进行的程序性电刺激显示,Notch被瞬时激活的小鼠对房性心律失常的敏感性增加。综上所述,这些结果表明,瞬时Notch激活会持续改变离子通道基因的表达和心房电生理,并容易导致心律失常。
结论:我们的数据提供了Notch信号调节成人心房肌内转录因子和离子通道基因表达的证据。凹口再激活会引起电变化,从而导致窦性心动过缓,窦性停顿以及对房性心律不齐的敏感性,这会导致表型类似于病态窦房结综合征。
更新日期:2017-08-31
down
wechat
bug