Balatskyi V. α-E-catenin in postnatal heart development

Thus, we employed a conditional knockout approach to explore the role of αE-catenin in the functioning of the adult heart and signaling networks that orchestrate myocardium metabolism. We found that αE-catenin plays an important role in the suppression of canonical Wnt- and Yap-dependent transcription in cardiomyocytes. Cardiospecific knockout of αE-catenin caused enlargement of the heart and atria, heart fibrosis, the upregulation of hypertrophic genes, and the dysregulation of fatty acid metabolism via Yap and β-catenin transcriptional activity. The robust activation of canonical Wnt and Yap negatively affected cardiomyocytes signaling machinery, specifically by downregulating the activity of main regulators of energy metabolism (adenosine monophosphate-activated protein kinase [AMPK] and peroxisome proliferator-activated receptor α [PPARα]) and dysregulating hypertrophic pathway activity (i.e., phosphatidylinositide 3-kinase [Pi3K]/Akt, cyclic adenosine monophosphate [cAMP]/protein kinase A [PKA], and MEK1/extracellular signal regulated kinase 1/2 [Erk1/2]). Moreover, αE-catenin downregulation negatively affected cardio-hemodynamic function and led to the inability of cardiomyocytes to adapt to physical loads via the PKA pathway. We found that the embryonic heart-specific ablation of αE-catenin led to the development of heart failure with age and premature death in mice. Thus, full or even partial αE-catenin gene dysfunction caused heart failure through canonical Wnt and Yap activation. In addition, we found that α-E-catenin knock out impairs maturation and terminal differentiation of neonatal cardiomyocytes via activation canonical Wnt- and Hippo-signaling pathways. The embryonic cardiospecific ablation of αE-catenin stimulates the proliferation of neonatal cardiomyocytes and attenuates their maturation (smaller cardiomyocytes and a lower level of binucleated cardiomyocytes) via the β-catenin-and Yap-dependent transcription activity. The signaling function of αE-catenin is crucially important for the postnatal heart maturation and function. Our data expand knowledge of the role of αE-catenin in regulating heart function. αEcatenin is involved in maintaining cell adhesion and modulating two critical signaling pathways (i.e., HIPPO and canonical Wnt). Thus, αE-catenin plays an important role in suppressing β-catenin- and Yap-dependent transcription in cardiomyocytes. The results suggest a molecular genetic mechanism of heart failure development due to the mutation in α-E-catenin our downregulation of its expression. Results obtained in this study, despite its fundamentality, may improve diagnostics of cardiovascular pathologies.