MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation
MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation
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MicroRNA-26 控制心房颤动中的前纤颤内向整流钾电流变化
DOI：
10.1172/jci62185
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
Nattel, Stanley
中科院分区：
文献类型：
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作者：
Luo, Xiaobin;Pan, Zhenwei;Nattel, Stanley
心房颤动（AF）是一种非常常见的心律失常，具有显著的发病率和死亡率。内向整流钾电流（I-K1）被认为是折返螺旋动力学的重要调节者，也是AF相关电重构的主要组成部分。microRNA-26（miR-26）被预测为靶向编码KIR2.1，KCNJ 2的基因。我们发现miR-26在AF动物和患者的心房样本中下调，并且这种下调伴随着I-K1/KIR2.1蛋白的上调。miR-26过表达抑制KCNJ 2/KIR2.1的表达。相反，miR-26敲低、抑制或结合位点突变增强了KCNJ 2/KIR2.1的表达，从而确立了KCNJ 2作为miR-26的靶点。内源性miR-26的敲低促进了小鼠的AF，而腺病毒介导的miR-26表达降低了AF的脆弱性。Kcnj 2特异性miR-masks消除了miR-26介导的Kcnj 2减少，消除了miR-26的保护作用，而Kcnj 2特异性miR-mimic的共注射预防了小鼠中miR-26敲低相关的AF。活化T细胞核因子（NFAT）是AF相关重塑中的已知作用因子，被发现负调控miR-26转录。我们的研究结果表明，miR-26控制KCNJ 2的表达，并表明这种dovvn调节可能促进AF。
Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (I-K1) 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 I-K1/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 dovvnregulation may promote AF.