Cardiomyocyte-specific deletion of \u03b2-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction

Jerry Wang,Wenbin Liang,Ying Xia,Aizhu Lu,Hongwei Wang,Peter Liu,Rob S Beanlands,Darryl R Davis

doi:10.1038/s41598-021-97176-9

Abstract

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K+ channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.

Highlights

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI)
◂Figure 1. β-catenin knockout reduces the susceptibility to ventricular tachycardias after myocardial infarction. (A) To generate cardiomyocyte-specific β-catenin (Ctnnb1) knockout mice, Ctnnb1flox/flox mice were crossbred with αMHC-MerCreMer mice to obtain Ctnnb1flox/flox;αMHC-MerCreMer+/− mice, which were treated with tamoxifen for deletion of exons 2–6 generating Ctnnb[1] null allele due to the loss of the translational start site
In the present study we demonstrated for the first time that mice with cardiomyocyte-specific deletion of β-catenin have reduced susceptibility to ventricular tachyarrhythmias at 8 weeks after MI, which is associated with attenuated structural remodeling

Summary

Introduction

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations. In mice with αMHC-Cre mediated β-catenin deletion, which made the cells non-responsive to Wnt stimulation, the scar size after MI was smaller which was associated with enhanced differentiation of a cardiac progenitor population (marked as αMHC+/ GATA4+/Tbx5+, but cTnT−) into small cTnT+ cardiomyocytes in the infarcted r egion[32]

Objectives

Methods

Findings

Conclusion