A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation

Calore, Martina; Lorenzon, Alessandra; Vitiello, Libero; Poloni, Giulia; Khan, Mohsin A.F.; Beffagna, Giorgia; Dazzo, Emanuela; Sacchetto, Claudia; Polishchuk, Roman; Sabatelli, Patrizia; Doliana, Roberto; Carnevale, Daniela; Lembo, Giuseppe; Bonaldo, Paolo; Windt, León J. De; Braghetta, Paola; Rampazzo, Alessandra

doi:10.1093/cvr/cvy253

Cited by 46 publications

(37 citation statements)

References 48 publications

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“…in cardiac fibrosis formation has been proven (Chelko et al, 2016;Calore et al, 2019;Zheng et al, 2019). If activation of these pathways indeed is preceded by increased ROS levels, ATP release, P2X, P2Y, and/or A2AR activation would be an interesting topic for upcoming studies.…”

Section: Ros-induced Fibroblast Differentiation In Acmmentioning

confidence: 95%

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

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Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease, associated with ventricular arrhythmias, fibrofatty replacement of the myocardial mass and an increased risk of sudden cardiac death (SCD). Malignant ventricular arrhythmias and SCD largely occur in the pre-clinical phase of the disease, before overt structural changes occur. To prevent or interfere with ACM disease progression, more insight in mechanisms related to electrical instability are needed. Currently, numerous studies are focused on the link between cardiac arrhythmias and metabolic disease. In line with that, a potential role of mitochondrial dysfunction in ACM pathology is unclear and mitochondrial biology in the ACM heart remains understudied. In this review, we explore mitochondrial dysfunction in relation to arrhythmogenesis, and postulate a link to typical hallmarks of ACM. Mitochondrial dysfunction depletes adenosine triphosphate (ATP) production and increases levels of reactive oxygen species in the heart. Both metabolic changes affect cardiac ion channel gating, electrical conduction, intracellular calcium handling, and fibrosis formation; all well-known aspects of ACM pathophysiology. ATP-mediated structural remodeling, apoptosis, and mitochondria-related alterations have already been shown in models of PKP2 dysfunction. Yet, the limited amount of experimental evidence in ACM models makes it difficult to determine whether mitochondrial dysfunction indeed precedes and/or accompanies ACM pathogenesis. Nevertheless, current experimental ACM models can be very useful in unraveling ACM-related mitochondrial biology and in testing potential therapeutic interventions.

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Section: Ros-induced Fibroblast Differentiation In Acmmentioning

confidence: 95%

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

et al. 2019

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“…A subsequent study evaluated 11 circulating miRNAs on 28 AC patients with definite diagnosis, 11 with borderline/possible AC diagnosis, and 23 had IVT, showing that four miRNAs (miR-144-3p, miR-145-5p, miR-185-5p, and miR-494) were significantly overexpressed in definite AC patients; specifically, miR-494 showed higher circulating levels in definite AC patients with recurrent ventricular arrhythmias after ablation (AUC = 0.832) [24]. More recently, the miRNA expression profile of a transgenic mouse model with the human DSG2 Q558* truncated protein showed three DE miRNAs when comparing the left ventricle and RV; specifically, miR-217-5p and miR-708-5p were upregulated and miR-499-5p were downregulated in the mouse RV [30].…”

Section: Previous Studies On Mirna In Acmentioning

confidence: 99%

“…In silico target prediction was performed while using DIANA mirPath v3 [28], a web-miRNA targets prediction server based on experimentally validated (TarBase v7.0) and theoretical (microT-CDS) miRNA:gene interactions, providing pathways that were enriched with targeted genes of DE miRNAs. Additionally, miRTarBase v2018 [30] was interrogated for experimentally validated targeted genes of miRNAs, and they were subsequently analysed on NetworkAnalyst.…”

Section: In Silico Target Predictionmentioning

confidence: 99%

A microRNA Expression Profile as Non-Invasive Biomarker in a Large Arrhythmogenic Cardiomyopathy Cohort

Marinas

Celeghin

Cason

et al. 2020

IJMS

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Arrhythmogenic Cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease. Half of AC patients harbour private desmosomal gene variants. Although microRNAs (miRNAs) have emerged as key regulator molecules in cardiovascular diseases and their involvement, correlated to phenotypic variability or to non-invasive biomarkers, has been advanced also in AC, no data are available in larger disease cohorts. Here, we propose the largest AC cohort unbiased by technical and biological factors. MiRNA profiling on nine right ventricular tissue, nine blood samples of AC patients, and four controls highlighted 10 differentially expressed miRNAs in common. Six of these were validated in a 90-AC patient cohort independent from genetic status: miR-122-5p, miR-133a-3p, miR-133b, miR-142-3p, miR-182-5p, and miR-183-5p. This six-miRNA set showed high discriminatory diagnostic power in AC patients when compared to controls (AUC-0.995), non-affected family members of AC probands carrying a desmosomal pathogenic variant (AUC-0.825), and other cardiomyopathy groups (Hypertrophic Cardiomyopathy: AUC-0.804, Dilated Cardiomyopathy: AUC-0.917, Brugada Syndrome: AUC-0.981, myocarditis: AUC-0.978). AC-related signalling pathways were targeted by this set of miRNAs. A unique set of six-miRNAs was found both in heart-tissue and blood samples of AC probands, supporting its involvement in disease pathogenesis and its possible role as a non-invasive AC diagnostic biomarker.

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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%

“…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%

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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A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation

Cited by 46 publications

References 48 publications

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

Mitochondrial Dysfunction as Substrate for Arrhythmogenic Cardiomyopathy: A Search for New Disease Mechanisms

A microRNA Expression Profile as Non-Invasive Biomarker in a Large Arrhythmogenic Cardiomyopathy Cohort

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

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