Exosomal MALAT1 from Rapid Electrical Stimulation-Treated Atrial Fibroblasts Enhances Sox-6 Expression by Downregulating miR-499a-5p

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 23; p. 1942
• Main Authors: Chuang, Cheng-Yen, Wang, Bao-Wei, Yu, Ying-Ju, Fang, Wei-Jen, Lin, Chiu-Mei, Shyu, Kou-Gi, Chua, Su-Kiat
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2024; MDPI
• Subjects: Adenocarcinoma; Analysis; Apoptosis; Apoptosis - genetics; Arrhythmia; Atrial fibrillation; Atrial Fibrillation - genetics; Atrial Fibrillation - metabolism; Atrial Fibrillation - pathology; Cardiac arrhythmia; Cell culture; Chromosome 5; Down-Regulation - genetics; Electric Stimulation; Electrical stimuli; Enzymes; Exosomes - metabolism; Fibroblasts; Fibroblasts - metabolism; Gene expression; Gene Expression Regulation; Genes; Health aspects; Heart; Heart Atria - metabolism; Humans; Luciferase; MALAT1; Metastases; microRNA-499a-5p; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular modelling; Morbidity; Pathogenesis; Plasmids; Polymerase chain reaction; Protocol; rapid electrical stimulation; Reagents; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; siRNA; sox-6; SOXD Transcription Factors - genetics; SOXD Transcription Factors - metabolism; Thermal cycling; Transcription factors; Vectors (Biology); California; United States; Massachusetts; Taiwan; United States > US; apoptosis; microRNA-499a-5p; MALAT1; rapid electrical stimulation; sox-6
• DOI: 10.3390/cells13231942
• ISSN: 2073-4409

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. Rapid electrical stimulation (RES) of atrial fibroblasts plays a crucial role in AF pathogenesis, but the underlying molecular mechanisms remain unclear. This study investigates the regulatory axis involving MALAT1, miR-499a-5p, and SOX6 in human cardiac fibroblasts from adult atria (HCF-aa) under RES conditions. Methods: HCF-aa were subjected to RES at 0.5 V/cm and 10 Hz. The expression levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), miR-499a-5p, and SRY-Box Transcription Factor 6 (SOX6) were measured using qPCR and Western blot analyses. Luciferase reporter assays were performed to confirm target relationships. The effects of MALAT1 siRNA, miR-499a-5p mimics/inhibitors, and SOX6 overexpression on gene expression and apoptosis were assessed. Results: RES increased exosomal MALAT1 expression, peaking at 2 h. MiR-499a-5p levels initially increased, then decreased at 2 h, coinciding with peak MALAT1 expression. SOX6 mRNA and protein levels increased, peaking at 4 and 6 h, respectively. Luciferase assays confirmed MALAT1 and SOX6 as miR-499a-5p targets. MALAT1 knockdown increased miR-499a-5p levels and reduced SOX6 expression. MiR-499a-5p overexpression decreased SOX6 levels and inhibited RES-induced apoptosis. Conclusion: In HCF-aa under RES, increased exosomal MALAT1 expression counteracts miR-499-5p’s suppression of SOX6, suggesting that MALAT1-containing exsosomes derived from HCF-aa may offer a novel cell-free therapeutic approach for AF.