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 β-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/β-catenin and RhoA-ROCK pathways must be inactive for a significant increase of PPARγ expression, suggesting that a crosstalk mechanism might be responsible for mediating ARVC pathogenesis.

Deciphering the role of wnt and rho signaling pathway in ipsc-derived arvc cardiomyocytes by in silico mathematical modeling / Parrotta, E. I.; Procopio, A.; Scalise, S.; Esposito, C.; Nicoletta, G.; Santamaria, G.; De Angelis, M. T.; Dorn, T.; Moretti, A.; Laugwitz, K. -L.; Montefusco, F.; Cosentino, C.; Cuda, G.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:4(2021), pp. 1-19. [10.3390/ijms22042004]

Deciphering the role of wnt and rho signaling pathway in ipsc-derived arvc cardiomyocytes by in silico mathematical modeling

Montefusco F.;
2021

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 β-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/β-catenin and RhoA-ROCK pathways must be inactive for a significant increase of PPARγ expression, suggesting that a crosstalk mechanism might be responsible for mediating ARVC pathogenesis.
Deciphering the role of wnt and rho signaling pathway in ipsc-derived arvc cardiomyocytes by in silico mathematical modeling / Parrotta, E. I.; Procopio, A.; Scalise, S.; Esposito, C.; Nicoletta, G.; Santamaria, G.; De Angelis, M. T.; Dorn, T.; Moretti, A.; Laugwitz, K. -L.; Montefusco, F.; Cosentino, C.; Cuda, G.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 22:4(2021), pp. 1-19. [10.3390/ijms22042004]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/254864
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