Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation.
Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation.
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DOI：
10.1016/j.stemcr.2021.04.019
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发表时间：
2021-06-08
影响因子：
5.9
通讯作者：
Darbar D
中科院分区：
文献类型：
--
作者：
Hong L;Zhang M;Ly OT;Chen H;Sridhar A;Lambers E;Chalazan B;Youn SW;Maienschein-Cline M;Feferman L;Ong SG;Wu JC;Rehman J;Darbar D
编码心脏钠通道的SCN 5A突变与家族性房颤（AF）有关，但其潜在的病理生理机制和治疗意义仍不清楚。为了表征AF连锁SCN 5A突变的发病机制，我们使用CRISPR-Cas9基因编辑从携带SCN 5A突变（E428 K和N470 K）的两种激酶和同基因对照产生了患者特异性诱导多能干细胞衍生的心房心肌细胞（iPSC-aCM）。我们发现，突变型AF iPSC-aCM表现出自发的致心律失常活性，具有搏动间不规则性、延长的动作电位持续时间和触发样搏动。单细胞记录揭示了在异源表达模型中不存在的AF iPSC-aCM中增强的晚期钠电流（INa，L）。AF iPSC-aCM的基因表达谱显示了一氧化氮（NO）介导的信号通路的差异表达，该信号通路是增强的INa，L。我们显示患者特异性AF iPSC-aCM表现出AF连锁的SCN 5A突变的显著体外电生理表型，并且转录组学分析支持NO信号传导途径调节INa，L并触发AF。编码心脏钠通道的基因SCN 5A中的突变，与家族性房颤（AF）SCN 5A突变型iPSC衍生的心房心肌细胞（aCM）有关携带SCN 5A突变的AF iPSC-aCM表现出增强的晚期钠电流（INa，L）。显示患者特异性iPSC-aCM表现出AF连锁突变的显著电生理表型，其在异源表达系统中产生最小变化，并发现增强的晚期钠电流（INa，L），NO信号传导的转录调节，这些发现不仅提供了对AF相关突变的潜在细胞机制的见解，而且还强调了潜在的机制-治疗这种常见的心律失常
Mutations in SCN5A, encoding the cardiac sodium channel, are linked with familial atrial fibrillation (AF) but the underlying pathophysiologic mechanisms and implications for therapy remain unclear. To characterize the pathogenesis of AF-linked SCN5A mutations, we generated patient-specific induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) from two kindreds carrying SCN5A mutations (E428K and N470K) and isogenic controls using CRISPR-Cas9 gene editing. We showed that mutant AF iPSC-aCMs exhibited spontaneous arrhythmogenic activity with beat-to-beat irregularity, prolonged action potential duration, and triggered-like beats. Single-cell recording revealed enhanced late sodium currents (INa,L) in AF iPSC-aCMs that were absent in a heterologous expression model. Gene expression profiling of AF iPSC-aCMs showed differential expression of the nitric oxide (NO)-mediated signaling pathway underlying enhanced INa,L. We showed that patient-specific AF iPSC-aCMs exhibited striking in vitro electrophysiological phenotype of AF-linked SCN5A mutations, and transcriptomic analyses supported that the NO signaling pathway modulated the INa,L and triggered AF. Mutations in SCN5A, the gene encoding the cardiac sodium channel, have been linked with familial atrial fibrillation (AF) SCN5A mutant iPSC-derived atrial cardiomyocytes (aCMs) exhibited arrhythmogenic activity with an AF-like phenotype AF iPSC-aCMs carrying SCN5A mutation exhibited enhanced late sodium currents (INa,L) Nitric oxide-mediated signaling pathway modulated enhanced INa,L in AF iPSC-aCMs Hong et al. showed that patient-specific iPSC-aCMs exhibited striking electrophysiological phenotype of an AF-linked mutation that produced minimal changes in heterologous expression system, and discovered a link between enhanced late sodium currents (INa,L), transcriptional regulation of NO signaling, and triggered AF. These findings not only provide insights into underlying cellular mechanisms of AF-linked mutations but also highlight potential mechanism-based therapies for this common arrhythmia.
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DOI：
10.1109/iembs.2011.6091155
发表时间：
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期刊：
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