Cardiospecific deletion of αE-catenin leads to heart failure and lethality in mice.

Abstract

αE-catenin is a component of adherens junctions that link the cadherin-catenin complex to the actin cytoskeleton. The signaling function of this protein was recently revealed. In the present study, we investigated the role of αE-catenin in the pathogenesis of heart failure. We mated αE-catenin conditional knockout mice with αMHC-Cre mice and evaluated their mutant offspring. We found that αE-catenin knockout caused enlargement of the heart and atria, fibrosis, the upregulation of hypertrophic genes, and the dysregulation of fatty acid metabolism via the transcriptional activity of Yap and β-catenin. The activation of canonical Wnt and Yap decreased the activity of main regulators of energy metabolism (i.e., adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor α) and dysregulated hypertrophic pathway activity (i.e., phosphatidylinositide 3-kinase/Akt, cyclic adenosine monophosphate/protein kinase A, and MEK1/extracellular signal regulated kinase 1/2). The loss of αE-catenin also negatively affected cardio-hemodynamic function via the protein kinase A pathway. Overall, we found that the embryonic heart-specific ablation of αE-catenin leads to the development of heart failure with age and premature death in mice. Thus, αE-catenin appears to have a crucial signaling function in the postnatal heart, and the dysfunction of this gene causes heart failure through canonical Wnt and Yap activation.