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Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere wi...

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Autores principales: Vasireddi, Sunil K., Sattayaprasert, Prasongchai, Yang, Dandan, Dennis, Adrienne T., Bektik, Emre, Fu, Ji-dong, Mackall, Judith A., Laurita, Kenneth R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9604824/
https://www.ncbi.nlm.nih.gov/pubmed/36294819
http://dx.doi.org/10.3390/jpm12101680
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author Vasireddi, Sunil K.
Sattayaprasert, Prasongchai
Yang, Dandan
Dennis, Adrienne T.
Bektik, Emre
Fu, Ji-dong
Mackall, Judith A.
Laurita, Kenneth R.
author_facet Vasireddi, Sunil K.
Sattayaprasert, Prasongchai
Yang, Dandan
Dennis, Adrienne T.
Bektik, Emre
Fu, Ji-dong
Mackall, Judith A.
Laurita, Kenneth R.
author_sort Vasireddi, Sunil K.
collection PubMed
description Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with β-catenin–dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC. Cardiac myocyte monolayers co-cultured for 2–4 days with mesenchymal stem cells (MSC) were derived from human-induced pluripotent stem cells with the ARVC5 TMEM43 p.Ser358Leu mutation. The TMEM43 mutation in myocyte co-cultures alone had no significant effect on impulse conduction velocity (CV) or APD. In contrast, when co-cultures were exposed to pro-adipogenic factors for 2–4 days, CV and APD were significantly reduced compared to controls by 49% and 31%, respectively without evidence of adipogenesis. Additionally, these arrhythmia substrates coincided with a significant reduction in IGF-1 expression in MSCs and were mitigated by IGF-1 treatment. These findings suggest that the onset of enhanced adipogenic signaling may be a mechanism of early arrhythmogenesis, which could lead to personalized treatment for arrhythmias associated with TMEM43 and other ARVC mutations.
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spelling pubmed-96048242022-10-27 Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC Vasireddi, Sunil K. Sattayaprasert, Prasongchai Yang, Dandan Dennis, Adrienne T. Bektik, Emre Fu, Ji-dong Mackall, Judith A. Laurita, Kenneth R. J Pers Med Article Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with β-catenin–dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC. Cardiac myocyte monolayers co-cultured for 2–4 days with mesenchymal stem cells (MSC) were derived from human-induced pluripotent stem cells with the ARVC5 TMEM43 p.Ser358Leu mutation. The TMEM43 mutation in myocyte co-cultures alone had no significant effect on impulse conduction velocity (CV) or APD. In contrast, when co-cultures were exposed to pro-adipogenic factors for 2–4 days, CV and APD were significantly reduced compared to controls by 49% and 31%, respectively without evidence of adipogenesis. Additionally, these arrhythmia substrates coincided with a significant reduction in IGF-1 expression in MSCs and were mitigated by IGF-1 treatment. These findings suggest that the onset of enhanced adipogenic signaling may be a mechanism of early arrhythmogenesis, which could lead to personalized treatment for arrhythmias associated with TMEM43 and other ARVC mutations. MDPI 2022-10-09 /pmc/articles/PMC9604824/ /pubmed/36294819 http://dx.doi.org/10.3390/jpm12101680 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vasireddi, Sunil K.
Sattayaprasert, Prasongchai
Yang, Dandan
Dennis, Adrienne T.
Bektik, Emre
Fu, Ji-dong
Mackall, Judith A.
Laurita, Kenneth R.
Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC
title Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC
title_full Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC
title_fullStr Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC
title_full_unstemmed Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC
title_short Adipogenic Signaling Promotes Arrhythmia Substrates before Structural Abnormalities in TMEM43 ARVC
title_sort adipogenic signaling promotes arrhythmia substrates before structural abnormalities in tmem43 arvc
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9604824/
https://www.ncbi.nlm.nih.gov/pubmed/36294819
http://dx.doi.org/10.3390/jpm12101680
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