Huo R, Hu C, Zhao L, Sun L, Wang N, Lu Y, Ye B, Deb A, Li F, Xu H

?-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear.The purpose of this study was to investigate the role of ?-catenin gain of function in the development of arrhythmia.A mouse model with a ...

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conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3-deleted and stabilized ?-catenin (?-cat?E3) was used to determine the role of ?-catenin gain of function in the regulation of cardiac rhythm.Western blotting showed ?-cat?E3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3-/- and CTNNB1 E3+/- mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel ?1 to ?4 expression in these hearts. Immunofluorescence revealed accumulation of ?-cat?E3 in the nuclei of CTNNB1 E3-/- cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of ?-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that ?-cat?E3 interacted with TCF4 in CTNNB1 E3-/- cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3-/- ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3-/-, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged.Enhancement of ?-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.

Date: Nov. 01, 2019

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