Qiao Yun, Lipovsky Catherine, Hicks Stephanie, Bhatnagar Somya, Li Gang, Khandekar Aditi, Guzy Robert, Woo Kel Vin, Nichols Colin G, Efimov Igor R, Rentschler Stacey
From the Department of Medicine, Cardiovascular Division (Y.Q., C.L., S.H., S.B., G.L., A.K., S.R.), Department of Biomedical Engineering (Y.Q., G.L., S.R.), Department of Developmental Biology (C.L., S.B., S.R.), Department of Pediatrics (K.V.W.), and Department of Cell Biology (C.G.N.), Washington University in St Louis, MO; Department of Medicine, University of Chicago, IL (R.G.); and Department of Biomedical Engineering, The George Washington University, Science and Engineering Hall, Washington DC (Y.Q., I.R.E.).
Circ Res. 2017 Aug 18;121(5):549-563. doi: 10.1161/CIRCRESAHA.116.310396. Epub 2017 Jul 3.
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 (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 (NK2 homeobox 5), , and 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 (Nav1.5) and (connexin 40), are persistently downregulated long after a transient Notch pulse. Consistent with the reduction in transcript, Notch induces global changes in the atrial action potential, including a reduced . 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.
Notch信号通路在心脏发育过程中调控心脏传导，在成人心室中，损伤诱导的Notch信号重新激活会引发整体转录和表观遗传变化。
确定Notch信号重新激活是否会稳定改变心房离子通道基因表达和心律失常易感性。
为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胞内结构域[iNICD]）在成年心肌中短暂激活Notch信号。与对照组相比，iNICD小鼠出现显著的心率减慢和频繁的窦性停搏。iNICD小鼠的心房结构正常，窦房结结构保留，但窦房结和心房传导的关键转录调节因子的表达，包括（NK2同源盒5）、和失调。为确定诱导的电变化是否稳定，我们短暂激活Notch，随后进行长时间洗脱期，观察到除心率降低外，心房传导速度持续慢于对照组。与传导减慢一致，编码心房传导速度分子决定因素的基因，包括（Nav1.5）和（连接蛋白40），在短暂的Notch脉冲后很长时间内持续下调。与转录本减少一致，Notch诱导心房动作电位的整体变化，包括降低。此外，在小鼠肺静脉附近进行程序性电刺激显示，在Notch被短暂激活的小鼠中，心房心律失常的易感性增加。综上所述，这些结果表明短暂的Notch激活会持续改变离子通道基因表达和心房电生理，并易引发致心律失常底物。
我们的数据提供了证据，表明Notch信号通路调节成年心房心肌内的转录因子和离子通道基因表达。Notch信号重新激活诱导电变化，导致窦性心动过缓、窦性停搏以及心房心律失常易感性，这促成了一种类似于病态窦房结综合征的表型。
