Open AccessEpicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation
Author(s) -
van den Berg Nicoline W. E.,
Kawasaki Makiri,
Fabrizi Benedetta,
Nariswari Fransisca A.,
Verduijn Arianne C.,
Neefs Jolien,
Wesselink Robin,
AlShama Rushd F. M.,
van der Wal Allard C.,
de Boer Onno J.,
Aten Jan,
Driessen Antoine H. G.,
Jongejan Aldo,
de Groot Joris R.
Publication year - 2021
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.558
Subject(s) - extracellular matrix , downregulation and upregulation , versican , microbiology and biotechnology , angiogenesis , tenascin c , fibroblast , epithelial–mesenchymal transition , cancer research , mesenchymal stem cell , cell growth , medicine , biology , proteoglycan , cell culture , gene , biochemistry , genetics
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.