Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation
Abstract Background Improved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies. Methods We present transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF, and p...
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Wiley
2021
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oai:doaj.org-article:1856597343d24eb6845f5da16fe68c382021-11-30T07:25:37ZEpicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation2001-132610.1002/ctm2.558https://doaj.org/article/1856597343d24eb6845f5da16fe68c382021-11-01T00:00:00Zhttps://doi.org/10.1002/ctm2.558https://doaj.org/toc/2001-1326Abstract Background Improved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies. Methods We present transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF, and persistent AF (total n = 64). RNA expression levels were validated in the same and an independent cohort with qPCR. Biological processes were assessed with histological and immunohistochemical analyses. Results In AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial‐to‐mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast‐like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis, and endothelial signaling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast‐like cells and extracellular matrix gene expression including enhanced tenascin‐C, thrombospondins, biglycan, and versican. Morphological analyses discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signaling pathways, including cell–matrix interactions, PI3K‐AKT, and Notch signaling that could regulate mesenchymal cell activation, were upregulated. Conclusion Our results suggest that EMT and endothelial cell proliferation work in concert and characterize the (myo)fibroblast recruitment and ECM remodeling of AF. These processes could guide future research toward the discovery of targets for AF therapy.Nicoline W. E. van den BergMakiri KawasakiBenedetta FabriziFransisca A. NariswariArianne C. VerduijnJolien NeefsRobin WesselinkRushd F. M. Al‐ShamaAllard C. van der WalOnno J. de BoerJan AtenAntoine H. G. DriessenAldo JongejanJoris R. de GrootWileyarticleangiogenesisarrhythmiasatrial fibrillationatrial remodelingepithelial‐to‐mesenchymal transitionextracellular matrixMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
angiogenesis arrhythmias atrial fibrillation atrial remodeling epithelial‐to‐mesenchymal transition extracellular matrix Medicine (General) R5-920 |
| spellingShingle |
angiogenesis arrhythmias atrial fibrillation atrial remodeling epithelial‐to‐mesenchymal transition extracellular matrix Medicine (General) R5-920 Nicoline W. E. van den Berg Makiri Kawasaki Benedetta Fabrizi Fransisca A. Nariswari Arianne C. Verduijn Jolien Neefs Robin Wesselink Rushd F. M. Al‐Shama Allard C. van der Wal Onno J. de Boer Jan Aten Antoine H. G. Driessen Aldo Jongejan Joris R. de Groot Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| description |
Abstract Background Improved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies. Methods We present transcriptome sequencing of atrial tissues of patients without AF, with paroxysmal AF, and persistent AF (total n = 64). RNA expression levels were validated in the same and an independent cohort with qPCR. Biological processes were assessed with histological and immunohistochemical analyses. Results In AF patients, epicardial cell gene expression decreased, contrasting with an upregulation of epithelial‐to‐mesenchymal transition (EMT) and mesenchymal cell gene expression. Immunohistochemistry demonstrated thickening of the epicardium and an increased proportion of (myo)fibroblast‐like cells in the myocardium, supporting enhanced EMT in AF. We furthermore report an upregulation of endothelial cell proliferation, angiogenesis, and endothelial signaling. EMT and endothelial cell proliferation concurred with increased interstitial (myo)fibroblast‐like cells and extracellular matrix gene expression including enhanced tenascin‐C, thrombospondins, biglycan, and versican. Morphological analyses discovered increased and redistributed glycosaminoglycans and collagens in the atria of AF patients. Signaling pathways, including cell–matrix interactions, PI3K‐AKT, and Notch signaling that could regulate mesenchymal cell activation, were upregulated. Conclusion Our results suggest that EMT and endothelial cell proliferation work in concert and characterize the (myo)fibroblast recruitment and ECM remodeling of AF. These processes could guide future research toward the discovery of targets for AF therapy. |
| format |
article |
| author |
Nicoline W. E. van den Berg Makiri Kawasaki Benedetta Fabrizi Fransisca A. Nariswari Arianne C. Verduijn Jolien Neefs Robin Wesselink Rushd F. M. Al‐Shama Allard C. van der Wal Onno J. de Boer Jan Aten Antoine H. G. Driessen Aldo Jongejan Joris R. de Groot |
| author_facet |
Nicoline W. E. van den Berg Makiri Kawasaki Benedetta Fabrizi Fransisca A. Nariswari Arianne C. Verduijn Jolien Neefs Robin Wesselink Rushd F. M. Al‐Shama Allard C. van der Wal Onno J. de Boer Jan Aten Antoine H. G. Driessen Aldo Jongejan Joris R. de Groot |
| author_sort |
Nicoline W. E. van den Berg |
| title |
Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| title_short |
Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| title_full |
Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| title_fullStr |
Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| title_full_unstemmed |
Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| title_sort |
epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/1856597343d24eb6845f5da16fe68c38 |
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