Loss of cardiac Wnt/β-catenin signalling in desmoplakin-deficient AC8 zebrafish models is rescuable by genetic and pharmacological intervention

Giuliodori, A.; Beffagna, Giorgia; Marchetto, Giulia; Fornetto, Chiara; Vanzi, Francesco; Toppo, Stefano; Facchinello, Nicola; Santimaria, M; Vettori, Andrea; Rizzo, Stefania; Barbera, Mila Della; Pilichou, Kalliopi; Argenton, Francesco; Thiene, Gaetano; Tiso, Natascia; Basso, Cristina

doi:10.1093/cvr/cvy057

Cited by 43 publications

(44 citation statements)

References 54 publications

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“…Desmosomes also help localize the actin‐regulatory machinery including Rho‐GTPases, which might further impact the organisation and function of the adherens junctions associated actin cytoskeleton and contractile apparatus. Desmosome components also regulate multiple other signalling pathways including GSK3beta/Wnt, p38/TGFbeta and Ras/Erk2 . Coupling with these pathways regulates multiple endpoints in skin and heart, including cell fate, differentiation, and fibrotic gene expression.…”

Section: What Is the Role Of The Desmosome In Arrhythmogenic Cardiomymentioning

confidence: 99%

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Elliott

Anastasakis

Asimaki

et al. 2019

European J of Heart Fail

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109

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It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

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Section: What Is the Role Of The Desmosome In Arrhythmogenic Cardiomymentioning

confidence: 99%

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Elliott

Anastasakis

Asimaki

et al. 2019

European J of Heart Fail

Self Cite

109

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“…Moreover, a zebrafish model of DSP deficiency has been recently generated for in vivo cell signaling screen, using pathway-specific reporter transgenes. Out of nine considered, three pathways (Wnt/β-catenin, TGFβ/Smad3, and Hippo/YAP-TAZ) were significantly altered, with Wnt as the most dramatically affected (Giuliodori et al, 2018). The findings of all these papers point to Wnt/β-catenin as the final common pathway underlying the ACM pathogenesis, independently from the causal gene.…”

Section: Wnt Signaling In Acm and Smdmentioning

confidence: 96%

Arrhythmogenic Cardiomyopathy and Skeletal Muscle Dystrophies: Shared Histopathological Features and Pathogenic Mechanisms

Gao¹,

Chen²,

Nardo³

et al. 2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease characterized by fibrotic or fibrofatty myocardial replacement, associated with an increased risk of ventricular arrhythmias and sudden cardiac death. Originally described as a disease of the right ventricle, ACM is currently recognized as a biventricular entity, due to the increasing numbers of reports of predominant left ventricular or biventricular involvement. Research over the last 20 years has significantly advanced our knowledge of the etiology and pathogenesis of ACM. Several etiopathogenetic theories have been proposed; among them, the most attractive one is the dystrophic theory, based on the observation of similar histopathological features between ACM and skeletal muscle dystrophies (SMDs), such as progressive muscular degeneration, inflammation, and tissue replacement by fatty and fibrous tissue. This review will describe the pathophysiological and molecular similarities shared by ACM with SMDs.

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“…AKT was found inhibited, leading to GSK-3β activation and consequent inhibition of β-catenin activity in this mouse model [ 23 ]. Furthermore, the pathogenic role of inhibition of Wnt signaling in ACM has been shown in an ACM transgenic mouse model with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 with the Q558* nonsense mutation [ 20 ] and in a zebrafish model of DSP deficiency [ 21 ]. Collectively, these results suggest that alteration of Wnt signaling pathway could be an important mechanism underlying the fibrofatty infiltration in both desmosomal and non-desmosomal ACM.…”

Section: Molecular Pathogenic Pathwaysmentioning

confidence: 99%

“…In addition, activation of the Hippo signaling was responsible for Wnt inactivation through sequestration of β-catenin in the cytosol by pYAP. A recent study on a novel zebrafish model of DSP deficiency has shown that Hippo/YAP-TAZ, Wnt/β-catenin and TGFβ/Smad3 were significantly altered [ 21 ]. The findings of these studies strongly indicate a mechanistic association among mutations in desmosomal components, Hippo pathway activation, Wnt inhibition and enhanced adipogenesis in ACM.…”

Section: Molecular Pathogenic Pathwaysmentioning

confidence: 99%

“…Several molecular and cellular mechanisms have been proposed to explain the pathogenesis of ACM. It has been shown that the presence of the ACM causal mutations induce activation of the Hippo signaling and inhibition of the Wnt signaling and activation of transforming growth factor beta (TGFβ) signaling [ 1 , 2 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Recent studies suggest electric instability in early stages of ACM may be the consequence of dysregulation of ion channels and Ca 2+ signaling machinery, not only as direct effect of causal mutations located in genes encoding components of the Ca 2+ homeostasis, but also as consequence of mutations in desmosomal genes [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

Gao

Puthenvedu

Lombardi

et al. 2020

IJMS

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Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

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Loss of cardiac Wnt/β-catenin signalling in desmoplakin-deficient AC8 zebrafish models is rescuable by genetic and pharmacological intervention

Cited by 43 publications

References 54 publications

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Arrhythmogenic Cardiomyopathy and Skeletal Muscle Dystrophies: Shared Histopathological Features and Pathogenic Mechanisms

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

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