Abstract
BackgroundThe potential mechanisms of microRNA-1 (miR-1) in the electrical remodeling of atrial fibrillation remain unclear. The purpose of this study was to evaluate the effects of miR-1 on the atrial effective refractory period (AERP) in a right atrial tachypacing model and to elucidate the potential mechanisms.Methods and ResultsQRT-PCR and western blot were used to detect the expression of the miR-1, KCNE1, and KCNB2 genes after 1-week of right atrial tachypacing in New Zealand white rabbits. The AERP was measured using a programmable multichannel stimulator, and atrial fibrillation was induced by burst stimulation in vivo. The slowly activating delayed rectifier potassium current (IKs) and AERP in atrial cells were measured by whole cell patch clamp in vitro. Right atrial tachypacing upregulated miR-1 expression and downregulated KCNE1 and KCNB2 in this study, while the AERP was decreased and the atrial IKs increased. The downregulation of KCNE1 and KCNB2 levels was greater when miR-1 was further upregulated through in vivo lentiviral infection. Electrophysiological tests indicated a shorter AERP, a great increase in the IKs and a higher atrial fibrillation inducibility. In addition, similar results were found when the levels of KCNE1 and KCNB2 were downregulated by small interfering RNA while keeping miR-1 level unaltered. Conversely, knockdown of miR-1 by anti-miR-1 inhibitor oligonucleotides alleviated the downregulation of KCNE1 and KCNB2, the shortening of AERP, and the increase in the IKs. KCNE1 and KCNB2 as the target genes for miR-1 were confirmed by luciferase activity assay.ConclusionsThese results indicate that miR-1 accelerates right atrial tachypacing-induced AERP shortening by targeting potassium channel genes, which further suggests that miR-1 plays an important role in the electrical remodeling of atrial fibrillation and exhibits significant clinical relevance as a potential therapeutic target for atrial fibrillation.
Highlights
Atrial fibrillation (AF) is one of the most common arrhythmias and is associated with a substantial morbidity, mortality, and socioeconomic burden [1]
The effects of atrial tachypacing (A-TP) First, we investigated the effects of A-TP on miR-1 levels and observed an approximately 1.6-fold increase after pacing (Figure 1A)
Animals were processed according to the A-TP model described in the Materials and Methods section, and the atrial effective refractory period (AERP) of right atrium (RA) was measured using S1-S2 programmed electrical stimulation (PES) at the following 3 time points in vivo: before pacing (“a” in Figure 3A), before infection control/recombinant lentiviral vectors (LVs) (“b”), and 1-week after infection (“c”)
Summary
Atrial fibrillation (AF) is one of the most common arrhythmias and is associated with a substantial morbidity, mortality, and socioeconomic burden [1]. Differences between messenger ribonucleic acid (mRNA) levels and the corresponding proteins have been observed frequently in gene expression studies [3], and this regulatory mechanism at the post-transcriptional level suggests that microRNAs (miRNAs) should play an important role in AF. The purpose of this study was to evaluate the effects of miR-1 on the atrial effective refractory period (AERP) in a right atrial tachypacing model and to elucidate the potential mechanisms. Right atrial tachypacing upregulated miR-1 expression and downregulated KCNE1 and KCNB2 in this study, while the AERP was decreased and the atrial IKs increased. Conclusions: These results indicate that miR-1 accelerates right atrial tachypacing-induced AERP shortening by targeting potassium channel genes, which further suggests that miR-1 plays an important role in the electrical remodeling of atrial fibrillation and exhibits significant clinical relevance as a potential therapeutic target for atrial fibrillation
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