Inhibition of β-catenin Protects Mouse Hearts From Ventricular Arrhythmias After Myocardial Infarction Independent of Ion Channel Gene Changes

Abstract

The Wnt/β-catenin signaling regulates ion channel gene expressions in cardiomyocytes. Because Wnt/β-catenin signaling is activated in myocardial infarction (MI), this study aims to investigate if β-catenin inhibition 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 week-8 after MI, associated with attenuated structural remodeling (reduced scar size and attenuated left ventricle dilation) as compared to WT. However, at the subacute phase (week-1) and chronic phase (week-8) after MI, Wnt/β-catenin signaling activation was found in non-cardiomyocytes, but not in cardiomyocytes. Downregulations of Scn5a (encoding Nav1.5) and Gja1 (encoding Cx43) were found at week-1 but not at week-8, while downregulations of K+ channel genes were present at both week-1 and -8. Consistent with no activation of Wnt/β-catenin pathway in cardiomyocytes at week-1 and -8, these alterations in ion channel/transporter genes were not different between KO and WT mice. This study demonstrated that mice with cardiomyocyte-specific β-catenin deletion have reduced VT susceptibility after MI which is caused by attenuated structural remodeling, instead of alterations in ion channel gene expressions.