Almazov National Medical Research Centre, Saint-Petersburg, Russia.
Almazov National Medical Research Centre, Saint-Petersburg, Russia; Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, Saint-Petersburg, Russia.
Biochim Biophys Acta Mol Basis Dis. 2020 Nov 1;1866(11):165915. doi: 10.1016/j.bbadis.2020.165915. Epub 2020 Aug 6.
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.
与心律失常性心肌病相关的桥粒蛋白基因突变通常与 Wnt/β-连环蛋白信号异常和钠电流密度降低有关。GSK3B 抑制剂被报道可恢复各种心律失常性心肌病模型中的钠电流并改善心脏功能，但这种作用的机制仍不清楚。我们假设桥粒蛋白、信号通路和心脏钠通道之间存在串扰。
为了揭示心律失常性心肌病的分子机制，我们建立了基于人诱导多能干细胞的该病理模型。来自携带 PKP2 基因两个遗传变异的患者的 iPSC 衍生的心肌细胞表明，由于移码变异导致的 PKP2 杂合不足，与从第二个等位基因表达的错义变异相结合，与 Wnt/β-连环蛋白活性降低和钠电流减少有关。测试了不同的方法来恢复受损的心肌细胞功能，包括野生型 PKP2 转导、GSK3B 抑制和 Wnt/β-连环蛋白信号调节。GSK3B 抑制导致患者特异性心肌细胞中 Wnt/β-连环蛋白信号活性和钠电流密度的恢复，而 GSK3B 激活导致钠电流密度降低。此外，我们发现抑制 GSK3B 后，钠电流通过 Wnt/β-连环蛋白非依赖性机制得到恢复。
我们提出，GSK3B-Wnt/β-连环蛋白信号通路的改变导致钠电流的调节，暗示其在心律失常性心肌病的分子发病机制中的作用。
