Inhibition of Wnt/β-catenin signaling significantly rescued Nav1.5 defects and arrhythmic phenotypes in iPSC-CMs derived from a patient with SCN5A-related Brugada syndrome.
Does inhibition of Wnt/β-catenin signaling rescue Nav1.5 defects and arrhythmic phenotypes in SCN5A-related Brugada syndrome iPSC-CMs?
Aberrant activation of Wnt/β-catenin signaling contributes to the pathogenesis of SCN5A-related Brugada syndrome, and its inhibition rescues Nav1.5 defects and arrhythmic phenotypes in patient-derived iPSC-CMs.
Abstract Background 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. Methods 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. Results 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 (Na v 1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Na v 1.5 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 Na v 1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A -encoded Na v 1.5 interacts with β-catenin, and reduced expression of Na v 1.5 leads to re-localization of β-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/β-catenin signaling to suppress SCN5A transcription. Conclusions 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.
Cai et al. (Fri,) conducted a other in SCN5A-related Brugada syndrome (n=4). Wnt/β-catenin signaling inhibition (IWR-1) vs. DMSO (vehicle) was evaluated on Rescue of Nav1.5 defects and arrhythmic phenotype. Inhibition of Wnt/β-catenin signaling significantly rescued Nav1.5 defects and arrhythmic phenotypes in iPSC-CMs derived from a patient with SCN5A-related Brugada syndrome.