Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation

Liang Hong; Meihong Zhang; Olivia Thao Ly; Hanna Chen; Arvind Sridhar; Erin Lambers; Brandon Chalazan; Seock Won Youn; Mark Maienschein-Cline; Leonid Feferman; Sang Ging Ong; Joseph C. Wu; Jalees Rehman; Dawood Darbar

doi:10.1016/j.stemcr.2021.04.019

Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation

Liang Hong^*, Meihong Zhang, Olivia Thao Ly, Hanna Chen, Arvind Sridhar, Erin Lambers, Brandon Chalazan, Seock Won Youn, Mark Maienschein-Cline, Leonid Feferman, Sang Ging Ong, Joseph C. Wu, Jalees Rehman, Dawood Darbar^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

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 (I_Na,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 I_Na,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 I_Na,L and triggered AF.

Original language	English (US)
Pages (from-to)	1542-1554
Number of pages	13
Journal	Stem cell reports
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.stemcr.2021.04.019
State	Published - Jun 8 2021

Keywords

atrial fibrillation
cardiac sodium channel
iPSCs
mutations
nitric oxide

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2021.04.019

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Hong, L., Zhang, M., Ly, O. T., Chen, H., Sridhar, A., Lambers, E., Chalazan, B., Youn, S. W., Maienschein-Cline, M., Feferman, L., Ong, S. G., Wu, J. C., Rehman, J., & Darbar, D. (2021). Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation. Stem cell reports, 16(6), 1542-1554. https://doi.org/10.1016/j.stemcr.2021.04.019

@article{1f92eace0f424fb4923ee03e0222ef72,

title = "Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation",

abstract = "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.",

keywords = "atrial fibrillation, cardiac sodium channel, iPSCs, mutations, nitric oxide",

author = "Liang Hong and Meihong Zhang and Ly, {Olivia Thao} and Hanna Chen and Arvind Sridhar and Erin Lambers and Brandon Chalazan and Youn, {Seock Won} and Mark Maienschein-Cline and Leonid Feferman and Ong, {Sang Ging} and Wu, {Joseph C.} and Jalees Rehman and Dawood Darbar",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jun,

day = "8",

doi = "10.1016/j.stemcr.2021.04.019",

language = "English (US)",

volume = "16",

pages = "1542--1554",

journal = "Stem cell reports",

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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 2021, 'Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation', Stem cell reports, vol. 16, no. 6, pp. 1542-1554. https://doi.org/10.1016/j.stemcr.2021.04.019

TY - JOUR

T1 - Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation

AU - Hong, Liang

AU - Zhang, Meihong

AU - Ly, Olivia Thao

AU - Chen, Hanna

AU - Sridhar, Arvind

AU - Lambers, Erin

AU - Chalazan, Brandon

AU - Youn, Seock Won

AU - Maienschein-Cline, Mark

AU - Feferman, Leonid

AU - Ong, Sang Ging

AU - Wu, Joseph C.

AU - Rehman, Jalees

AU - Darbar, Dawood

PY - 2021/6/8

Y1 - 2021/6/8

N2 - 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.

AB - 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.

KW - atrial fibrillation

KW - cardiac sodium channel

KW - iPSCs

KW - mutations

KW - nitric oxide

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UR - http://www.scopus.com/inward/citedby.url?scp=85107115493&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2021.04.019

DO - 10.1016/j.stemcr.2021.04.019

M3 - Article

C2 - 34019817

AN - SCOPUS:85107115493

SN - 2213-6711

VL - 16

SP - 1542

EP - 1554

JO - Stem cell reports

JF - Stem cell reports

IS - 6

ER -

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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