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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2020
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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. |
format | Online Article Text |
id | pubmed-7526536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
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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