Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy

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.

Keywords: Wnt; arrhythmogenic cardiomyopathy; microRNAs; molecular pathogenesis; β-catenin.

Figure 1. Schematic representation of β-catenin–mediated canonical Wnt pathway

(Left) In the absence of Wnt ligands, the Wnt signaling is suppressed. Cytosolic β-catenin is phosphorylated by a destruction complex composed of Axin, APC, GSK3β and CK1 and then ubiquitinated and targeted to proteasomal degradation. Into the nucleus, the transcription of Wnt target genes is repressed by Groucho binding to Tcf/Lef. (Right) Wnt activation. The binding of Wnt ligands to their receptors Fzd/LRP5/6/Dvl, determines the disruption of the β-catenin destruction complex, thus inducing the stabilization of the protein, which can translocate into the nucleus, function as a cofactor for Tcf/Lef and activate Wnt target genes (APC, adenomatous polyposis coli; β-cat, β-catenin; CK1, casein kinase cell factor/lymphoid enhancer-binding factor).

Figure 2. Models of AC pathogenesis

AC gene mutations involve area composita and desmosome proteins (asterisks) and lead to abnormalities in intercalated disc (ID) consisting of cell adhesion defects, gap junction and ion channel remodelling. (A) Mutations in ID proteins can result also in the perturbation of the Wnt/β-catenin signaling. (B) Wnt/β-catenin signaling is suppressed in concomitance with the activation of Hippo pathway [93]. The impaired localization of phosphorylated protein kinase C-α to the perturbed IDs is associated with activation of neurofibromin 2 (NF2) and results in cascade phosphorylation leading to increased phospho-Yes-associated protein (pYAP) and its retention in the cytoplasm. pYAP interacts with β-catenin (β-cat), which is not able to translocate into the nucleus and, as a consequence, the expression of the effectors of both Hippo and canonical Wnt pathways (TEAD and Tcf/Lef, respectively) is suppressed and adipogenesis is enhanced (B1). Other experimental data reveal that loss of plakoglobin leads to the activation of AKT and the subsequent inhibition of glycogen synthase kinase 3β (GSK3β) resulting in the stabilization of β-cat and its translocation in the nucleus. Here, β-cat interacts with Tcf/Lef causing the increase of the expression of c-myc, c-fos, and cyclin D1, as well as cardiac hypertrophy [98] (B2). The disruption of junction integrity can result in increased presence of β-catenin at IDs without the involvement of Wnt/β-catenin signaling. However, increased expression of transforming growth factor β-1 (TGFβ1), phospho-SMAD2 (pSMAD2), and Pai1 is consistent with the activation of TGFβ pathway responsible for the progressive fibrosis in AC hearts [99] (B3) (DSC2, desmocollin-2; DSG2, desmoglein-2; DSP, desmoplakin; PKP2, plakophilin-2; DES, desmin; N-cad, N-cadherin; αT-cat, αT-catenin; αE-cat, αE-catenin; Tcf/Lef, T cell factor/lymphoid enhancer-binding factor; TEAD, SV40 transcriptional enhancer factor domain).