Regulation of the SK3 channel by microRNA-499—Potential role in atrial fibrillation

Background MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3 , the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF. Objectives To evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression. Methods Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by using microRNA arrays. Potential targets of microRNAs were predicted by using software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by using luciferase reporter assay and by using Argonaute pull-down assay. Results Twenty-one microRNAs showed significant (>2-fold) changes in AF. MicroRNA 499 (miR-499) was upregulated by 2.33-fold ( P P Conclusion Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.