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

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.

WNT/β‐catenin pathway is a key regulator of cardiac function and energetic metabolism

“…182,183 Interestingly, βcatenin deletion is also cardioprotective and reduces susceptibility to arrhythmias after myocardial infarction, likely through the attenuation of structural remodeling. 184 Proper βcatenin cascade activity maintains the resident CPC population in the adult heart. 142 The prolonged stabilization of βcatenin, starting from late embryogenesis, aggravates myocardial infarction and enhances mortality by impairing the differentiation of resident CPCs.…”

“…Inducible cardiac‐specific GSK3β deletion also improves heart healing after infarction and limits heart dilatation 182,183 . Interestingly, β‐catenin deletion is also cardioprotective and reduces susceptibility to arrhythmias after myocardial infarction, likely through the attenuation of structural remodeling 184 …”

The role of β-catenin in cardiac diseases

“…The inhibition of Nav1.5 by Wnt/β-catenin is responsible for arrhythmia in the acute phase after MI, while the mechanism of arrhythmia in the chronic phase after MI is more likely to involve myocardial remodeling rather than changes in ion channels. Jerry Wang et al ( Wang J. et al, 2021 ) observed a reduction in the occurrence of arrhythmias in β-catenin-knockout (KO) mice at 8 weeks after MI, which was consistent with reduced scar size and ventricular dilation, and Na + /K + channel genes were not different between WT (wild type) and KO mice ( Wang J. et al, 2021 ).…”

Proteomic analysis of transcription factors involved in the alteration of ischemic mouse heart as modulated by MSC exosomes

“…Wnt/β-catenin signaling which plays an important role in development of the heart [ 38 ]. Wnt signaling has been shown to be re-activated in the ischemic myocardium, both in the infarct and peri-infarct areas [ 39 , 40 ]. Renin-angiotensin system activation also leads to activation of Wnt signaling/β-catenin signaling [ 41 ].…”