Epicardial and endothelial cell activation concurs with extracellular matrix remodeling in atrial fibrillation

Abstract

BackgroundImproved understanding of the interconnectedness of structural remodeling processes in atrial fibrillation (AF) in patients could identify targets for future therapies.MethodsWe 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.ResultsIn 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.ConclusionOur 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.

Research Progress on Natural Products’ Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

“…After seven days of intraperitoneal injecting PNS (100 μ g/g), atrial fibrillation induced by ACh-CaCl2 mixed solution was significantly inhibited with effective refractory period prolonged, and the duration of atrial fibrillation shortened [ 50 ]. By activating the PI3K-AKT signaling pathway, the infiltration of inflammatory cells into cardiomyocytes and blood vessels and the deposition of collagen fibers around blood vessels were inhibited, with myocardial fibrosis improved in rats with atrial fibrillation [ 51 ].…”

Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers

“…Primary cilium is a small organelle that extends from a cell's surface, and functions as a chemo-and mechano-sensors. Our proteome and transcriptome analysis of atrial tissue of patients with or without AF (non-AF) shows that the gene-sets of ciliogenesis, including IFT88, are down-regulated in AF compared to non-AF patients (Kawasaki et al, 2021;van den Berg et al, 2021). The dysregulation of primary cilia has been implicated in the fibrosis formation in various tissues, such as liver and kidney (Teves et al, 2019;Collins and Wann, 2020).…”

3D Spheroids — a Cellular Model for Studying the Effects of Hypoxia on the Epicardial Microenvironment

“…Ключевым индуктором, запускающим развитие фиброза, является гипоксия [5,6]. Ее воздействие вызывает стабилизацию гипоксияиндуцированных факторов (HIF) в фибробластообразующих клетках, в частности -в клетках эпикарда, обеспечивает их активацию, формирование фибробластов и прогрессирование фиброза [7][8][9]. Однако механизмы такой регуляции остаются малоизученными в связи с анатомическими ограничениями для доступа к эпикарду и отсутствием релевантных клеточных моделей.…”