Morishima Masaki, Iwata Eriko, Nakada Chisato, Tsukamoto Yoshiyuki, Takanari Hiroki, Miyamoto Shinji, Moriyama Masatsugu, Ono Katsushige
Department of Pathophysiology, Oita University School of Medicine.
Circ J. 2016 May 25;80(6):1346-55. doi: 10.1253/circj.CJ-15-1276. Epub 2016 May 13.
Atrial fibrillation (AF) begets AF in part due to atrial remodeling, the molecular mechanisms of which have not been completely elucidated. This study was conducted to identify microRNA(s) responsible for electrical remodeling in AF.
The expression profiles of 1205 microRNAs, in cardiomyocytes from patients with persistent AF and from age-, gender-, and cardiac function-matched control patients with normal sinus rhythm, were examined by use of a microRNA microarray platform. Thirty-nine microRNAs differentially expressed in AF patients' atria were identified, including miR-30d, as a candidate responsible for ion channel remodeling by in silico analysis. MiR-30d was significantly upregulated in cardiomyocytes from AF patients, whereas the mRNA and protein levels ofCACNA1C/Cav1.2 andKCNJ3/Kir3.1, postulated targets of miR-30d, were markedly reduced.KCNJ3/Kir3.1 expression was downregulated by transfection of the miR-30 precursor, concomitant with a reduction of the acetylcholine-sensitive inward-rectifier K(+)current (IK.ACh).KCNJ3/Kir3.1 (but notCACNA1C/Cav1.2) expression was enhanced by the knockdown of miR-30d. The Ca(2+)ionophore, A23187, induced a dose-dependent upregulation of miR-30d, followed by the suppression ofKCNJ3mRNA expression. Blockade of protein kinase C signaling blunted the [Ca(2+)]i-dependent downregulation of Kir3.1 via miR-30d.
The downward remodeling ofIK.AChis attributed, at least in part, to deranged Ca(2+)handling, leading to the upregulation of miR-30d in human AF, revealing a novel post-transcriptional regulation ofIK.ACh. (Circ J 2016; 80: 1346-1355).
心房颤动（AF）部分是由于心房重构导致的，其分子机制尚未完全阐明。本研究旨在确定导致AF电重构的微小RNA。
采用微小RNA微阵列平台检测了持续性AF患者及年龄、性别和心功能匹配的正常窦性心律对照患者心肌细胞中1205种微小RNA的表达谱。共鉴定出39种在AF患者心房中差异表达的微小RNA，其中包括miR-30d，通过计算机分析，其被认为是离子通道重构的候选因子。miR-30d在AF患者的心肌细胞中显著上调，而推测为miR-30d靶标的CACNA1C/Cav1.2和KCNJ3/Kir3.1的mRNA和蛋白水平则显著降低。转染miR-30前体可下调KCNJ3/Kir3.1的表达，并伴随乙酰胆碱敏感性内向整流钾电流（IK.ACh）的减少。敲低miR-30d可增强KCNJ3/Kir3.1（而非CACNA1C/Cav1.2）的表达。钙离子载体A23187可剂量依赖性地上调miR-30d，随后抑制KCNJ3 mRNA的表达。蛋白激酶C信号通路的阻断可减弱通过miR-30d介导的细胞内钙离子浓度([Ca(2+)])依赖性的Kir3.1下调。
IK.ACh的下调重塑至少部分归因于钙离子处理紊乱，导致人类AF中miR-30d上调，揭示了IK.ACh一种新的转录后调控机制。（《循环杂志》2016年；80: 1346 - 1355）
