AI Article Synopsis

  • Fibroblast-derived exosomes are shown to play a role in regulating heart cell electrical activity, particularly through the intermediate-conductance calcium-activated potassium channel (KCa3.1), which is involved in atrial electrical remodeling.
  • The study involved isolating heart cells from rats and using electrical stimulation to create a model of atrial fibrillation, with experiments designed to see how exosomes from fibroblasts influenced KCa3.1 and related mechanisms.
  • Findings indicated that increased exosome secretion during rapid heart pacing enhanced KCa3.1 expression and altered heart cell action potentials, while blocking KCa3.1 reduced action potential duration and potentially the risk of atrial fibrillation.

Article Abstract

Background: Fibroblast-derived exosomes can regulate the electrical remodeling of cardiomyocytes, and the intermediate-conductance calcium-activated potassium channel (KCa3.1) is important in atrial electrical remodeling. However, the underlying molecular mechanisms remain unclear. This study aimed to investigate the regulation of cardiac electrophysiology by exosomes linked to KCa3.1.

Methods: Atrial myocytes (AMs) and atrial fibroblasts were isolated from Sprague-Dawley suckling rats and cultured individually. The cellular atrial fibrillation (AF) model was established via electrical stimulation (1.0 v/cm, 10 Hz), and fibroblast-derived exosomes were isolated via ultracentrifugation. Exosomes were co-cultured with AMs to investigate their influences on KCa3.1 and the underlying mechanisms. Nanoparticle tracking analysis and transmission electron microscopy were used to measure exosome particle sizes and concentrations. Whole-cell patch clamp was applied to record the current density of KCa3.1 and action potential duration (APD). The expression of miR-21-5p was detected by reverse-transcription polymerase chain reaction (RT-PCR). Western blotting or immunofluorescence was used to measure the expression of exosomal markers, Akt phosphorylation, and KCa3.1.

Results: Rapid pacing promoted the secretion of exosomes from atrial fibroblasts and miR-21-5p expression in atrial fibroblasts and exosomes. KCa3.1 protein expression and current density significantly increased, and APD50 and APD90 were sharply shortened after rapid pacing in AMs. TRAM-34 (KCa3.1 blocker) extended APD and reduced susceptibility to AF. KCa3.1 and P-AKT expressions were amplified after co-culturing AMs with exosomes secreted by atrial fibroblasts. In contrast, the increase in KCa3.1 expression was reversed after the cells were co-cultured with exosomes secreted by atrial fibroblasts that were transfected with miR-21-5p inhibitors or after the use of LY294002, a PI3K/Akt pathway inhibitor.

Conclusions: Rapid pacing promoted the secretion of exosomes from fibroblasts, and miR-21-5p was upregulated in exosomes. Moreover, the miR-21-5p-enriched exosomes upregulated KCa3.1 expression in AMs via the PI3K/Akt pathway.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11260968PMC
http://dx.doi.org/10.1016/j.heliyon.2024.e33059DOI Listing

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