Enhancement of β-catenin/T-cell factor 4 signaling causes susceptibility to cardiac arrhythmia by suppressing NaV1.5 expression in mice

Heart Rhythm. 2019 Nov;16(11):1720-1728. doi: 10.1016/j.hrthm.2019.05.015. Epub 2019 May 22.

Abstract

Background: β-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.

Objective: The purpose of this study was to investigate the role of β-catenin gain of function in the development of arrhythmia.

Methods: A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3-deleted and stabilized β-catenin (β-catΔE3) was used to determine the role of β-catenin gain of function in the regulation of cardiac rhythm.

Results: Western blotting showed β-catΔE3 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 β1 to β4 expression in these hearts. Immunofluorescence revealed accumulation of β-catΔE3 in the nuclei of CTNNB1 E3-/- cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of β-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that β-catΔE3 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.

Conclusion: Enhancement of β-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.

Keywords: Cardiac arrhythmia; Na(+) channel; Na(V)1.5; TCF4; β-Catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / genetics*
  • Disease Models, Animal
  • Exons
  • Gain of Function Mutation*
  • Humans
  • Mice
  • Myocardial Ischemia / metabolism
  • Myocytes, Cardiac / metabolism
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Signal Transduction
  • Transcription Factor 7-Like 2 Protein / genetics*
  • Transcription Factor 7-Like 2 Protein / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, mouse
  • NAV1.5 Voltage-Gated Sodium Channel
  • Tcf7l2 protein, mouse
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin