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Wnt/beta-catenin signaling pathway plays essential roles in heart development as well as cardiac tissue homoeostasis in adults. Abnormal regulation of this signaling pathway is linked to a variety of cardiac disease conditions, including hypertrophy, fibrosis, arrhythmias, and infarction. Recent studies on genetically modified cellular and animal models document a crucial role of Wnt/beta-catenin signaling in the molecular pathogenesis of arrhythmogenic cardiomyopathy (AC), an inherited disease of intercalated discs, typically characterized by ventricular arrhythmias and progressive substitution of the myocardium with fibrofatty tissue. In this review, we summarize the conflicting published data regarding the Wnt/beta-catenin signaling contribution to AC pathogenesis and we report the identification of a new potential therapeutic molecule that prevents myocyte injury and cardiac dysfunction due to desmosome mutations in vitro and in vivo by interfering in this signaling pathway. Finally, we underline the potential function of microRNAs, epigenetic regulatory RNA factors reported to participate in several pathological responses in heart tissue and in the Wnt signaling network, as important modulators of Wnt/beta-catenin signaling transduction in AC.Elucidation of the precise regulatory mechanism of Wnt/beta-catenin signaling in AC molecular pathogenesis could provide fundamental insights for new mechanism-based therapeutic strategy to delay the onset or progression of this cardiac disease.

// Alessandra Lorenzon 1 , Martina Calore 2 , Giulia Poloni 1 , Leon J. De Windt 2 , Paola Braghetta 3 and Alessandra Rampazzo 1 1 University of Padua, Department of Biology, Padua, Italy 2 Maastricht University, Department of Cardiology, Maastricht, The Netherlands 3 University of Padua, Department of Molecular Medicine, Padua, Italy Correspondence to: Alessandra Rampazzo, email: alessandra.rampazzo@unipd.it Keywords: Wnt, β-catenin, microRNAs, arrhythmogenic cardiomyopathy, molecular pathogenesis Received: January 30, 2017 Accepted: April 14, 2017 Published: April 27, 2017 ABSTRACT Wnt/β-catenin signaling pathway plays essential roles in heart development as well as cardiac tissue homoeostasis in adults. Abnormal regulation of this signaling pathway is linked to a variety of cardiac disease conditions, including hypertrophy, fibrosis, arrhythmias, and infarction. Recent studies on genetically modified cellular and animal models document a crucial role of Wnt/β-catenin signaling in the molecular pathogenesis of arrhythmogenic cardiomyopathy (AC), an inherited disease of intercalated discs, typically characterized by ventricular arrhythmias and progressive substitution of the myocardium with fibrofatty tissue. In this review, we summarize the conflicting published data regarding the Wnt/β-catenin signaling contribution to AC pathogenesis and we report the identification of a new potential therapeutic molecule that prevents myocyte injury and cardiac dysfunction due to desmosome mutations in vitro and in vivo by interfering in this signaling pathway. Finally, we underline the potential function of microRNAs, epigenetic regulatory RNA factors reported to participate in several pathological responses in heart tissue and in the Wnt signaling network, as important modulators of Wnt/β-catenin signaling transduction in AC. Elucidation of the precise regulatory mechanism of Wnt/β-catenin signaling in AC molecular pathogenesis could provide fundamental insights for new mechanism-based therapeutic strategy to delay the onset or progression of this cardiac disease.