Sodium current abnormalities and deregulation of Wnt/β-catenin signaling in iPSC-derived cardiomyocytes generated from patient with arrhythmogenic cardiomyopathy harboring compound genetic variants in plakophilin 2 gene.

Mutations in desmosomal genes linked to arrhythmogenic cardiomyopathy are commonly associated with Wnt/β-catenin signaling abnormalities and reduction of the sodium current density. Inhibitors of GSK3B were reported to restore sodium current and improve heart function in various arrhythmogenic cardiomyopathy models, but mechanisms underlying this effect remain unclear. We hypothesized that there is a crosstalk between desmosomal proteins, signaling pathways, and cardiac sodium channels. To reveal molecular mechanisms of arrhythmogenic cardiomyopathy, we established human iPSC-based model of this pathology. iPSC-derived cardiomyocytes from patient carrying two genetic variants in PKP2 gene demonstrated that PKP2 haploinsufficiency due to frameshift variant, in combination with the missense variant expressed from the second allele, was associated with decreased Wnt/β-catenin activity and reduced sodium current. Different approaches were tested to restore impaired cardiomyocytes functions, including wild type PKP2 transduction, GSK3B inhibition and Wnt/β-catenin signaling modulation. Inhibition of GSK3B led to the restoration of both Wnt/β-catenin signaling activity and sodium current density in patient-specific cardiomyocytes while GSK3B activation led to the reduction of sodium current density. Moreover, we found that upon inhibition GSK3B sodium current was restored through Wnt/β-catenin-independent mechanism. We propose that alterations in GSK3B-Wnt/β-catenin signaling pathways lead to regulation of sodium current implying its role in molecular pathogenesis of arrhythmogenic cardiomyopathy. Unlabelled Image • PKP2 genetic variants are associated with decreased Wnt/β-catenin activity and reduced sodium current density • Inhibition of GSK3B restores both Wnt/β-catenin signaling activity and sodium current density • GSK3B activation leads to the reduction of sodium current density • Inhibition of GSK3B restores sodium current density through Wnt/β-catenin-independent mechanism [ABSTRACT FROM AUTHOR]