Research output: Contribution to journal › Article › Academic › peer-review
Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation. / van den Berg, Nicoline W E; Kawasaki, Makiri; Fabrizi, Benedetta et al.
In: Clinical and translational medicine, Vol. 11, No. 11, 11.2021, p. e558.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation
AU - van den Berg, Nicoline W E
AU - Kawasaki, Makiri
AU - Fabrizi, Benedetta
AU - Nariswari, Fransisca A
AU - Verduijn, Arianne C
AU - Neefs, Jolien
AU - Wesselink, Robin
AU - Al-Shama, Rushd F M
AU - van der Wal, Allard C
AU - de Boer, Onno J
AU - Aten, Jan
AU - Driessen, Antoine H G
AU - Jongejan, Aldo
AU - de Groot, Joris R
N1 - © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
U2 - 10.1002/ctm2.558
DO - 10.1002/ctm2.558
M3 - Article
C2 - 34841686
VL - 11
SP - e558
JO - Clinical and translational medicine
JF - Clinical and translational medicine
SN - 2001-1326
IS - 11
ER -
ID: 21273589