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

Rong Huo, Chaowei Hu, Limei Zhao, Lihua Sun, Ning Wang, Yan Lu, Bo Ye, Arjun Deb, Faqian Li, Haodong Xu

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1720-1728
Number of pages9
JournalHeart Rhythm
Volume16
Issue number11
DOIs
StatePublished - Nov 2019

Bibliographical note

Funding Information:
This study was supported by the National Institutes of Health (grants R01HL122793 [to Dr Xu] and R01HL111480 [to Dr Li]) and the Department of Pathology at the University of Washington Medical Center (to Dr Xu).

Keywords

  • Cardiac arrhythmia
  • Na channel
  • Na1.5
  • TCF4
  • β-Catenin

PubMed: MeSH publication types

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

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