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

Parrotta, Elvira Immacolata; Procopio, Anna; Scalise, Stefania; Esposito, Claudia; Nicoletta, Giovanni; Santamaria, Gianluca; Angelis, Maria Teresa De; Dorn, Tatjana; Moretti, Alessandra; Laugwitz, Karl‐Ludwig; Montefusco, Francesco; Cosentino, Carlo; Cuda, Giovanni

doi:10.3390/ijms22042004

Cited by 14 publications

(10 citation statements)

References 45 publications

(29 reference statements)

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“…In corneal epithelial cells, inhibition of ROCK led to a translocation of E-Cadherin to the cytoplasm (Anderson et al, 2002). Apart from that, using an in silico mathematical model, it has been suggested that ROCK plays a role in the pathogenesis of AC (Parrotta et al, 2021). Furthermore, inhibition of ROCK during early cardiac development did lead to AC in a murine model with a reduced localization of PG at the ICD (Ellawindy et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

Shoykhet

Dervishi

Menauer

et al. 2022

Preprint

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The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase, which is dysregulated in several kinds of cancer and heart diseases. Arrhythmogenic cardiomyopathy (AC) is a familial heart disease in part caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity, may provide potential new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of EGFR inhibition on cardiomyocyte cohesion under physiological and pathophysiological conditions using the murine plakoglobin knockout AC model, in which EGFR was upregulated. EGFR inhibition led to enhanced cardiomyocyte cohesion. Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2). Immunostaining and AFM revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly was observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to the cell borders. Thus, inhibiting EGFR, thereby stabilizing desmosome integrity, may provide new treatment options for AC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

Shoykhet

Dervishi

Menauer

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In embryonic heart, ROCK inhibition could lead to fibrofatty replacement of cardiomyocytes in the right ventricle of adult mice resulting in arrhythmogenic right ventricular cardiomyopathy ( 165 ). Mechanistically, both Wnt/β-catenin and RhoA/ROCK pathways must be inactive for a significant increase of PPARγ expression, which is responsible for mediating arrhythmogenic right ventricular cardiomyopathy pathogenesis ( 166 ). Moreover, in embryonic heart, the RhoA/ROCK/F-actin/MRTF-A/SRF pathway is essential to maintaining cell-cell contacts of developing cardiomyocytes and inhibiting this pathway during cardiomyocyte differentiation primes cardiac progenitors to switch to the brown/beige adipocyte lineage in response to adipogenesis-inducing signals ( 114 ).…”

Section: Cellular Actions Of Rock Signaling Pathways In Adipose Tissuementioning

confidence: 99%

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

Wei

Shi

2022

Front. Endocrinol.

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Obesity and associated complications increasingly jeopardize global health and contribute to the rapidly rising prevalence of type 2 diabetes mellitus and obesity-related diseases. Developing novel methods for the prevention and treatment of excess body adipose tissue expansion can make a significant contribution to public health. Rho kinase is a Rho-associated coiled-coil-containing protein kinase (Rho kinase or ROCK). The ROCK family including ROCK1 and ROCK2 has recently emerged as a potential therapeutic target for the treatment of metabolic disorders. Up-regulated ROCK activity has been involved in the pathogenesis of all aspects of metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. The RhoA/ROCK-mediated actin cytoskeleton dynamics have been implicated in both white and beige adipogenesis. Studies using ROCK pan-inhibitors in animal models of obesity, diabetes, and associated complications have demonstrated beneficial outcomes. Studies via genetically modified animal models further established isoform-specific roles of ROCK in the pathogenesis of metabolic disorders including obesity. However, most reported studies have been focused on ROCK1 activity during the past decade. Due to the progress in developing ROCK2-selective inhibitors in recent years, a growing body of evidence indicates more attention should be devoted towards understanding ROCK2 isoform function in metabolism. Hence, studying individual ROCK isoforms to reveal their specific roles and principal mechanisms in white and beige adipogenesis, insulin sensitivity, energy balancing regulation, and obesity development will facilitate significant breakthroughs for systemic treatment with isoform-selective inhibitors. In this review, we give an overview of ROCK functions in the pathogenesis of obesity and insulin resistance with a particular focus on the current understanding of ROCK isoform signaling in white and beige adipogenesis, obesity and thermogenesis in adipose tissue and other major metabolic organs involved in energy homeostasis regulation.

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“…In corneal epithelial cells, inhibition of ROCK led to a translocation of E-Cadherin to the cytoplasm (68). Apart from that, using an in silico model, it has been suggested that ROCK plays a role in the pathogenesis of AC (69).…”

Section: Discussionmentioning

confidence: 99%

EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

Shoykhet¹,

Dervishi²,

Menauer³

et al. 2023

JCI Insight

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Arrhythmogenic cardiomyopathy (AC) is a familial heart disease partly caused by impaired desmosome turnover. Thus, stabilization of desmosome integrity may provide potential new treatment options. Desmosomes, apart from cellular cohesion, provide the structural framework of a signaling hub. Here, we investigated the role of the epidermal growth factor receptor (EGFR) in cardiomyocyte cohesion. We inhibited EGFR under physiological and pathophysiological conditions using the murine plakoglobin knockout AC model, in which EGFR was upregulated. EGFR inhibition enhanced cardiomyocyte cohesion.Immunoprecipitation showed an interaction of EGFR and desmoglein 2 (DSG2).Immunostaining and AFM revealed enhanced DSG2 localization and binding at cell borders upon EGFR inhibition. Enhanced area composita length and desmosome assembly were observed upon EGFR inhibition, confirmed by enhanced DSG2 and desmoplakin (DP) recruitment to cell borders. PamGene Kinase assay performed in HL-1 cells treated with Erlotinib, an EGFR inhibitor, revealed upregulation of RhoA associated protein kinase (ROCK). Erlotinib-mediated desmosome assembly and cardiomyocyte cohesion were abolished upon ROCK inhibition. Thus, inhibiting EGFR, thereby stabilizing desmosome integrity via ROCK, might provide new treatment options for AC.

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

Cited by 14 publications

References 45 publications

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

EGFR inhibition led ROCK activation enhances desmosome assembly and cohesion in cardiomyocytes

Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis

EGFR inhibition leads to enhanced desmosome assembly and cardiomyocyte cohesion via ROCK activation

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