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Deciphering the Role of Wnt and Rho Signaling Pathway in iPSC-Derived ARVC Cardiomyocytes by In Silico Mathematical Modeling.


ABSTRACT: Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) is an inherited cardiac muscle disease linked to genetic deficiency in components of the desmosomes. The disease is characterized by progressive fibro-fatty replacement of the right ventricle, which acts as a substrate for arrhythmias and sudden cardiac death. The molecular mechanisms underpinning ARVC are largely unknown. Here we propose a mathematical model for investigating the molecular dynamics underlying heart remodeling and the loss of cardiac myocytes identity during ARVC. Our methodology is based on three computational models: firstly, in the context of the Wnt pathway, we examined two different competition mechanisms between ?-catenin and Plakoglobin (PG) and their role in the expression of adipogenic program. Secondly, we investigated the role of RhoA-ROCK pathway in ARVC pathogenesis, and thirdly we analyzed the interplay between Wnt and RhoA-ROCK pathways in the context of the ARVC phenotype. We conclude with the following remark: both Wnt/?-catenin and RhoA-ROCK pathways must be inactive for a significant increase of PPAR? expression, suggesting that a crosstalk mechanism might be responsible for mediating ARVC pathogenesis.

SUBMITTER: Parrotta EI 

PROVIDER: S-EPMC7923182 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Deciphering the Role of Wnt and Rho Signaling Pathway in iPSC-Derived ARVC Cardiomyocytes by In Silico Mathematical Modeling.

Parrotta Elvira Immacolata EI   Procopio Anna A   Scalise Stefania S   Esposito Claudia C   Nicoletta Giovanni G   Santamaria Gianluca G   De Angelis Maria Teresa MT   Dorn Tatjana T   Moretti Alessandra A   Laugwitz Karl-Ludwig KL   Montefusco Francesco F   Cosentino Carlo C   Cuda Giovanni G  

International journal of molecular sciences 20210218 4


Arrhythmogenic Right Ventricular cardiomyopathy (ARVC) is an inherited cardiac muscle disease linked to genetic deficiency in components of the desmosomes. The disease is characterized by progressive fibro-fatty replacement of the right ventricle, which acts as a substrate for arrhythmias and sudden cardiac death. The molecular mechanisms underpinning ARVC are largely unknown. Here we propose a mathematical model for investigating the molecular dynamics underlying heart remodeling and the loss o  ...[more]

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