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Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin

Arrhythmogenic cardiomyopathy (AC) is a heart disease often caused by mutations in genes coding for desmosomal proteins, including desmoglein-2 (DSG2), plakoglobin (PG), and desmoplakin (DP). Therapy is based on symptoms and limiting arrhythmia, because the mechanisms by which desmosomal components...

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Autores principales: Shoykhet, Maria, Trenz, Sebastian, Kempf, Ellen, Williams, Tatjana, Gerull, Brenda, Schinner, Camilla, Yeruva, Sunil, Waschke, Jens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526536/
https://www.ncbi.nlm.nih.gov/pubmed/32841221
http://dx.doi.org/10.1172/jci.insight.140066
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author Shoykhet, Maria
Trenz, Sebastian
Kempf, Ellen
Williams, Tatjana
Gerull, Brenda
Schinner, Camilla
Yeruva, Sunil
Waschke, Jens
author_facet Shoykhet, Maria
Trenz, Sebastian
Kempf, Ellen
Williams, Tatjana
Gerull, Brenda
Schinner, Camilla
Yeruva, Sunil
Waschke, Jens
author_sort Shoykhet, Maria
collection PubMed
description Arrhythmogenic cardiomyopathy (AC) is a heart disease often caused by mutations in genes coding for desmosomal proteins, including desmoglein-2 (DSG2), plakoglobin (PG), and desmoplakin (DP). Therapy is based on symptoms and limiting arrhythmia, because the mechanisms by which desmosomal components control cardiomyocyte function are largely unknown. A new paradigm could be to stabilize desmosomal cardiomyocyte adhesion and hyperadhesion, which renders desmosomal adhesion independent from Ca(2+). Here, we further characterized the mechanisms behind enhanced cardiomyocyte adhesion and hyperadhesion. Dissociation assays performed in HL-1 cells and murine ventricular cardiac slice cultures allowed us to define a set of signaling pathways regulating cardiomyocyte adhesion under basal and hyperadhesive conditions. Adrenergic signaling, activation of PKC, and inhibition of p38MAPK enhanced cardiomyocyte adhesion, referred to as positive adhesiotropy, and induced hyperadhesion. Activation of ERK1/2 paralleled positive adhesiotropy, whereas adrenergic signaling induced PG phosphorylation at S665 under both basal and hyperadhesive conditions. Adrenergic signaling and p38MAPK inhibition recruited DSG2 to cell junctions. In PG-deficient mice with an AC phenotype, only PKC activation and p38MAPK inhibition enhanced cardiomyocyte adhesion. Our results demonstrate that cardiomyocyte adhesion can be stabilized by different signaling mechanisms, which are in part offset in PG-deficient AC.
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spelling pubmed-75265362020-10-05 Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin Shoykhet, Maria Trenz, Sebastian Kempf, Ellen Williams, Tatjana Gerull, Brenda Schinner, Camilla Yeruva, Sunil Waschke, Jens JCI Insight Research Article Arrhythmogenic cardiomyopathy (AC) is a heart disease often caused by mutations in genes coding for desmosomal proteins, including desmoglein-2 (DSG2), plakoglobin (PG), and desmoplakin (DP). Therapy is based on symptoms and limiting arrhythmia, because the mechanisms by which desmosomal components control cardiomyocyte function are largely unknown. A new paradigm could be to stabilize desmosomal cardiomyocyte adhesion and hyperadhesion, which renders desmosomal adhesion independent from Ca(2+). Here, we further characterized the mechanisms behind enhanced cardiomyocyte adhesion and hyperadhesion. Dissociation assays performed in HL-1 cells and murine ventricular cardiac slice cultures allowed us to define a set of signaling pathways regulating cardiomyocyte adhesion under basal and hyperadhesive conditions. Adrenergic signaling, activation of PKC, and inhibition of p38MAPK enhanced cardiomyocyte adhesion, referred to as positive adhesiotropy, and induced hyperadhesion. Activation of ERK1/2 paralleled positive adhesiotropy, whereas adrenergic signaling induced PG phosphorylation at S665 under both basal and hyperadhesive conditions. Adrenergic signaling and p38MAPK inhibition recruited DSG2 to cell junctions. In PG-deficient mice with an AC phenotype, only PKC activation and p38MAPK inhibition enhanced cardiomyocyte adhesion. Our results demonstrate that cardiomyocyte adhesion can be stabilized by different signaling mechanisms, which are in part offset in PG-deficient AC. American Society for Clinical Investigation 2020-09-17 /pmc/articles/PMC7526536/ /pubmed/32841221 http://dx.doi.org/10.1172/jci.insight.140066 Text en © 2020 Shoykhet et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Shoykhet, Maria
Trenz, Sebastian
Kempf, Ellen
Williams, Tatjana
Gerull, Brenda
Schinner, Camilla
Yeruva, Sunil
Waschke, Jens
Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin
title Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin
title_full Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin
title_fullStr Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin
title_full_unstemmed Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin
title_short Cardiomyocyte adhesion and hyperadhesion differentially require ERK1/2 and plakoglobin
title_sort cardiomyocyte adhesion and hyperadhesion differentially require erk1/2 and plakoglobin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526536/
https://www.ncbi.nlm.nih.gov/pubmed/32841221
http://dx.doi.org/10.1172/jci.insight.140066
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