Abstract 2286: Critical Role of miRNA-101 in Atrial Electrical Remodeling in Experimental Atrial Fibrillation
Our recent studies have highlighted the role of mRNAs, a newly discovered class of small, non-protein-coding mRNAs, in controlling cardiac excitability under various pathological settings of the heart; yet the potential role of miRNAs in atrial fibrillation (AF) remained unexplored. AF is characterized by atrial remodeling process: the rapid atrial activation rate during AF can remodel the atrial electrophysiology favoring the recurrence and maintenance of AF. A prominent finding in this process is a shortening of refractory period favoring reentry. This is primarily because of a shortening of atrial action potential as a result of two critical changes: reduction of L-type Ca2+ current ICaL that serves to shorten the plateau duration and increases in inward rectifier K+ current IK1 current, which underlies the shortening of the terminal phase. We have previously identified miR-328 as a critical determinant for depressed ICaL in AF. We report here that miR-101 is a key factor for the upregulation of IK1 in AF. We first performed miRNA profiling to identify deregulated miRNAs in a canine model of AF induced by atrial tachypacing. We found miR-101 being downregulated by >65% in AF. We subsequently verified KCNJ2 encoding Kir2.1 protein for IK1 as a cognate target for miR-101. Transfection of miR-101 reduced Kir2.1 level whereas application of the miRNA-101 antisense (AMO-101) alone to knockdown the endogenous miR-101 up-regulated Kir2.1, indicating the relief of tonic repression of Kir2.1 by miR-101. Accordingly, miR-101 depressed whilst AMO-101 enhances, IK1 current density. We then characterized the core promoter of the miRNA-101 gene and identified NFAT, a transcription factor well implicated in AF, as a transcriptional repressor of the miR-101 gene. We therefore proposed that enhanced NFAT in AF downregulates miR-101 transcription, which results in relief of repression of KCNJ2 leading to an increase in IK1, creating the substrate for AF and AF remodeling.