%0 Journal Article
%T Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt/β-catenin signaling in SCN5A-related Brugada syndrome.
%A Cai D
%A Wang X
%A Sun Y
%A Fan H
%A Zhou J
%A Yang Z
%A Qiu H
%A Wang J
%A Su J
%A Gong T
%A Jiang C
%A Liang P
%J Stem Cell Res Ther
%V 14
%N 1
%D 2023 09 8
%M 37679791
%F 8.079
%R 10.1186/s13287-023-03477-3
%X Mutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/β-catenin signaling has been recently established. However, the role of Wnt/β-catenin signaling in BrS and underlying mechanisms remains unknown.<BR>Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp.<BR>BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/β-catenin signaling. Notably, inhibition of Wnt/β-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with β-catenin, and reduced expression of Nav1.5 leads to re-localization of β-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/β-catenin signaling to suppress SCN5A transcription.<BR>Our findings suggest that aberrant activation of Wnt/β-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/β-catenin as a potential therapeutic target.