title: MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation.
abstract: Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.1, KCNJ2. We found that miR-26 was downregulated in atrial samples from AF animals and patients and this downregulation was accompanied by upregulation of IK1/KIR2.1 protein. miR-26 overexpression suppressed expression of KCNJ2/KIR2.1. In contrast, miR-26 knockdown, inhibition, or binding-site mutation enhanced KCNJ2/KIR2.1 expression, establishing KCNJ2 as a miR-26 target. Knockdown of endogenous miR-26 promoted AF in mice, whereas adenovirus-mediated expression of miR-26 reduced AF vulnerability. Kcnj2-specific miR-masks eliminated miR-26-mediated reductions in Kcnj2, abolishing miR-26's protective effects, while coinjection of a Kcnj2-specific miR-mimic prevented miR-26 knockdown-associated AF in mice. Nuclear factor of activated T cells (NFAT), a known actor in AF-associated remodeling, was found to negatively regulate miR-26 transcription. Our results demonstrate that miR-26 controls the expression of KCNJ2 and suggest that this downregulation may promote AF.
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Luo
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.forename: Hongli
authors.initials: H
authors.lastname: Shan
authors.forename: Jiening
authors.initials: J
authors.lastname: Xiao
authors.forename: Xuelin
authors.initials: X
authors.lastname: Sun
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Huixian
authors.initials: H
authors.lastname: Lin
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.forename: Deli
authors.initials: D
authors.lastname: Dong
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Bai
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Lihua
authors.initials: L
authors.lastname: Sun
authors.forename: Hang
authors.initials: H
authors.lastname: Lu
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Luo
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D004285:Dogs; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology; D050778:NFATC Transcription Factors / Q000378:metabolism; D011188:Potassium / Q000737:chemistry; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D050778:NFATC Transcription Factors; D011188:Potassium; D024661:Potassium Channels, Inwardly Rectifying; C489457:KCNJ2 protein, human; C575188:KCNJ2 protein, rat; C489461:Kir2.1 channel; C556274:MIRN26 microRNA, rat; C528163:MIRN26 microRNA, human; C543693:Mirn26 microRNA, mouse
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