MicroRNA-1 Accelerates the Shortening of Atrial Effective Refractory Period by Regulating KCNE1 and KCNB2 Expression: An Atrial Tachypacing Rabbit Model

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.

Aloe-Emodin Relieves High-Fat Diet Induced QT Prolongation via MiR-1 Inhibition and IK1 Up-Regulation in Rats

“…Numerous studies suggest that miRNAs are implicated in the development of cardiovascular diseases [16,17]. Among them, many studies have demonstrated that miR-1 plays a critical role in the occurrence of both ventricular and atrial arrhythmias by post-transcriptionally modulating ion channels and proteins related to cardiac electrical activity [18][19][20]. Based on these findings, the present study was conducted to investigate the two aspects.…”

microRNA in Cardiovascular Aging and Age-Related Cardiovascular Diseases

“…In electrically tachypaced rabbits, miR-1 upregulation produced a reduction of the atrial ERP (213). Lu et al reported the reduction of intracellular Ca 2+ concentration, induced by miR-1, with protective effect against AF (214).…”

MicroRNAs and atrial fibrillation: mechanisms and translational potential

“…45,57,58 A 2013 report suggested that miR-1 upregulation abbreviates the atrial ERP in electrically-tachypaced rabbits by targeting, and potentially downregulating, the K + channel subunits encoded by KCNE1 (voltage-gated potassium channel subfamily E member 1, also known as minK) and KCNB2 (voltage-gated potassium channel subfamily B member 2, also known as K v 2.2), respectively. 59 However, KCNE1 is weakly expressed in rabbit hearts, 60 and no role for KCNB2 has been documented.…”