Voltage-gated sodium channels (VGSCs) are essential for the initiation and propagation of cardiac action potentials. NaV1.5 is the predominant pore-forming α-subunit in ventricular cardiomyocytes. NaV1.5 is modulated by auxiliary β subunits. Splice variants β1 and β1B are both encoded by the SCN1B gene, with identical N termini but unique C termini. SCN1B regulates NaV1.5 localization and function and participates in adhesion interactions at the plasma membrane. Others show that mouse cardiomyocytes lacking SCN1B are less resistant to oxidative stress. In this study, we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to compare wild-type (WT) cells and SCN1B knockout (KO) cells under oxidative stress. We assessed cellular susceptibility using live-dead staining after treatment with diamide, a thiol-oxidizing agent that causes ROS accumulation. Our results show KO cells exhibit significantly greater cell death than WT cells over 15 mins of diamide treatment. Furthermore, immunostaining revealed higher expression of antioxidant enzymes glutathione reductase (GSR) and superoxide dismutase 1 (SOD1) in WT cells, suggesting that SCN1B expression enhances the cellular antioxidant response. We then transduced SCN1B KO cells with either β1 or β1B only and recorded action potentials after diamide treatment. We found that the transduced cells both maintain normal action potential duration, while SCN1B KO cells have significantly decreased APD over 15 minutes of treatment. These findings extend previous animal-based observations into a human-specific model and demonstrate that SCN1B may lead to protective effects against oxidative stress in human cardiomyocytes. Given the association of SCN1B mutations with arrhythmogenic disorders, such as Brugada syndrome, this work highlights a possible role for SCN1B in maintaining redox balance and potentially cardiac rhythm stability. Future experiments will investigate the distinct roles of the β1 and β1B splice variants in regulating these processes.
Williams et al. (Sun,) studied this question.