Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

Abstract

Background: Clinical studies have shown that exosomes are associated with atrial fibrillation (AF). However, the roles and underlying mechanisms remain unclear. Hence, this study aimed to investigate the function of exosomes in AF development.Methods: Twenty beagles were randomly divided into the sham group (n = 6), the pacing group (n = 7), and the pacing + GW4869 group (n = 7). The pacing and GW4869 groups underwent rapid atrial pacing (450 beats/min) for 7 days. The GW4869 group received intravenous GW4869 injection (an inhibitor of exosome biogenesis/release, 0.3 mg/kg, once a day) during pacing. Electrophysiological measurements, transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT-PCR, Masson's staining, and immunohistochemistry were performed in this study.Results: Rapid atrial pacing increased the release of plasma and atrial exosomes. GW4869 treatment markedly suppressed AF inducibility and reduced the release of exosomes. After 7 days of pacing, the expression of transforming growth factor-β1 (TGF-β1), collagen I/III, and matrix metalloproteinases was enhanced in the atrium, and the levels of microRNA-21-5p (miR-21-5p) were upregulated in both plasma exosomes and the atrium, while the tissue inhibitor of metalloproteinase 3 (TIMP3), a target of miR-21-5p, showed a lower expression in the atrium. The administration of GW4869 abolished these effects.Conclusions: The blockade of exosome release with GW4869 suppressed AF by alleviating atrial fibrosis in a canine model, which was probably related to profibrotic miR-21-5p enriched in exosomes and its downstream TIMP3/TGF-β1 pathway.

Cardiac Fibroblasts Promote Ferroptosis in Atrial Fibrillation by Secreting Exo-miR-23a-3p Targeting SLC7A11

“…In addition, it has been reported macrophage exosomes transferred Ang IIR to lung fibroblasts mediating bleomycin-induced pulmonary fibrosis, which is damped by GW4869 [ 21 ]. Our previous study also confirmed that GW4869 reduced the induction of AF by inhibiting atrial fibrosis [ 22 ]. All these results suggest that in pathological condition, exosome secretion increased for intercellular communication leads to disease progression.…”

“…Meanwhile, previous studies found that the inhibitor of sphingomyelinase could alleviate the fibrosis [ 20 , 21 ]. In our recent study, we also found that blockade of exosome release suppressed AF and atrial fibrosis [ 22 ].…”

Can Extracellular Vesicles as Drug Delivery Systems Be a Game Changer in Cardiac Disease?

“…The few studies involving EVs and arrhythmias mainly focus on pathophysiology and diagnosis. Several studies have been reported on the diagnosis of atrial fibrillation and one of its causes, atrial fibrosis [141][142][143][144][145].…”

Extracellular Vesicles in Atrial Fibrillation—State of the Art

“…Another research group established that beagles undergoing rapid atrial pacing for 7 days showed a rise in the atrial and plasma EVs release; moreover, it was effectively hampered by GW4869, a commonly used agent inhibiting EVs generation. It was also suggested that miR-21-5p could play a role, as it was upregulated in both atrial and plasma EVs [ 20 ]. EVs originating from mouse adipose-tissue-derived mesenchymal stem cells and transfected with the X-inactive specific transcript (XIST) caused a decrease in inflammation and myocardial pyroptosis [ 21 ].…”