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The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions
Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Mice overexpressing transcription factor Fosl-2 (Fosl-2(tg)) represent animal model of SSc. Fosl-2(tg) mice showed interstitial card...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911788/ https://www.ncbi.nlm.nih.gov/pubmed/36759717 http://dx.doi.org/10.1038/s42003-023-04534-6 |
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author | Stellato, Mara Dewenter, Matthias Rudnik, Michal Hukara, Amela Özsoy, Çagla Renoux, Florian Pachera, Elena Gantenbein, Felix Seebeck, Petra Uhtjaerv, Siim Osto, Elena Razansky, Daniel Klingel, Karin Henes, Joerg Distler, Oliver Błyszczuk, Przemysław Kania, Gabriela |
author_facet | Stellato, Mara Dewenter, Matthias Rudnik, Michal Hukara, Amela Özsoy, Çagla Renoux, Florian Pachera, Elena Gantenbein, Felix Seebeck, Petra Uhtjaerv, Siim Osto, Elena Razansky, Daniel Klingel, Karin Henes, Joerg Distler, Oliver Błyszczuk, Przemysław Kania, Gabriela |
author_sort | Stellato, Mara |
collection | PubMed |
description | Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Mice overexpressing transcription factor Fosl-2 (Fosl-2(tg)) represent animal model of SSc. Fosl-2(tg) mice showed interstitial cardiac fibrosis, disorganized connexin-43/40 in intercalated discs and deregulated expression of genes controlling conduction system, and developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability. Following stimulation with isoproterenol Fosl-2(tg) mice showed impaired HR response. In contrast to Fosl-2(tg), immunodeficient Rag2(−/−)Fosl-2(tg) mice were protected from enhanced myocardial fibrosis and ECG abnormalities. Transcriptomics analysis demonstrated that Fosl-2-overexpression was responsible for profibrotic signature of cardiac fibroblasts, whereas inflammatory component in Fosl-2(tg) mice activated their fibrotic and arrhythmogenic phenotype. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions transcription factor Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress. |
format | Online Article Text |
id | pubmed-9911788 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99117882023-02-11 The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions Stellato, Mara Dewenter, Matthias Rudnik, Michal Hukara, Amela Özsoy, Çagla Renoux, Florian Pachera, Elena Gantenbein, Felix Seebeck, Petra Uhtjaerv, Siim Osto, Elena Razansky, Daniel Klingel, Karin Henes, Joerg Distler, Oliver Błyszczuk, Przemysław Kania, Gabriela Commun Biol Article Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Mice overexpressing transcription factor Fosl-2 (Fosl-2(tg)) represent animal model of SSc. Fosl-2(tg) mice showed interstitial cardiac fibrosis, disorganized connexin-43/40 in intercalated discs and deregulated expression of genes controlling conduction system, and developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability. Following stimulation with isoproterenol Fosl-2(tg) mice showed impaired HR response. In contrast to Fosl-2(tg), immunodeficient Rag2(−/−)Fosl-2(tg) mice were protected from enhanced myocardial fibrosis and ECG abnormalities. Transcriptomics analysis demonstrated that Fosl-2-overexpression was responsible for profibrotic signature of cardiac fibroblasts, whereas inflammatory component in Fosl-2(tg) mice activated their fibrotic and arrhythmogenic phenotype. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions transcription factor Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress. Nature Publishing Group UK 2023-02-09 /pmc/articles/PMC9911788/ /pubmed/36759717 http://dx.doi.org/10.1038/s42003-023-04534-6 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Stellato, Mara Dewenter, Matthias Rudnik, Michal Hukara, Amela Özsoy, Çagla Renoux, Florian Pachera, Elena Gantenbein, Felix Seebeck, Petra Uhtjaerv, Siim Osto, Elena Razansky, Daniel Klingel, Karin Henes, Joerg Distler, Oliver Błyszczuk, Przemysław Kania, Gabriela The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
title | The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
title_full | The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
title_fullStr | The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
title_full_unstemmed | The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
title_short | The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
title_sort | ap-1 transcription factor fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911788/ https://www.ncbi.nlm.nih.gov/pubmed/36759717 http://dx.doi.org/10.1038/s42003-023-04534-6 |
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