Department of Cardiology Heidelberg University Hospital Heidelberg Germany.
DZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim University of Heidelberg Germany.
J Am Heart Assoc. 2022 Apr 5;11(7):e023472. doi: 10.1161/JAHA.121.023472. Epub 2022 Mar 18.
Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. However, underlying molecular mechanisms are insufficiently understood. Previous studies suggested that microRNA (miRNA) dependent gene regulation plays an important role in the initiation and maintenance of AF. The 2-pore-domain potassium channel TASK-1 (tandem of P domains in a weak inward rectifying K channel-related acid sensitive K channel 1) is an atrial-specific ion channel that is upregulated in AF. Inhibition of TASK-1 current prolongs the atrial action potential duration to similar levels as in patients with sinus rhythm. Here, we hypothesize that miRNAs might be responsible for the regulation of that encodes for TASK-1. Methods and Results We selected miRNAs potentially regulating and studied their expression in atrial tissue samples obtained from patients with sinus rhythm, paroxysmal AF, or permanent/chronic AF. MiRNAs differentially expressed in AF were further investigated for their ability to regulate mRNA and TASK-1 protein expression in human induced pluripotent stem cells, transfected with miRNA mimics or inhibitors. Thereby, we observed that miR-34a increases TASK-1 expression and current and further decreases the resting membrane potential of oocytes, heterologously expressing hTASK-1. Finally, we investigated associations between miRNA expression in atrial tissues and clinical parameters of our patient cohort. A cluster containing AF stage, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, left atrial diameter, atrial COL1A2 (collagen alpha-2(I) chain), and TASK-1 protein level was associated with increased expression of miR-25, miR-21, miR-34a, miR-23a, miR-124, miR-1, and miR-29b as well as decreased expression of miR-9 and miR-485. Conclusions These results suggest an important pathophysiological involvement of miRNAs in the regulation of atrial expression of the TASK-1 potassium channel in patients with atrial cardiomyopathy.
心房颤动（AF）是最常见的持续性心律失常。然而，其潜在的分子机制尚未完全阐明。先前的研究表明，microRNA（miRNA）依赖性基因调控在 AF 的发生和维持中起着重要作用。2 孔域钾通道 TASK-1（串联 P 结构域在弱内向整流钾通道相关酸敏感钾通道 1）是一种在 AF 中上调的心房特异性离子通道。抑制 TASK-1 电流可使心房动作电位持续时间延长至与窦性节律患者相似的水平。在这里，我们假设 miRNA 可能负责调节编码 TASK-1 的基因。
我们选择了可能调节 的 miRNA，并研究了它们在窦性节律、阵发性 AF 或永久性/慢性 AF 患者的心房组织样本中的表达。在转染 miRNA 模拟物或抑制剂的人诱导多能干细胞中，进一步研究了在 AF 中差异表达的 miRNA 调节 mRNA 和 TASK-1 蛋白表达的能力。因此，我们观察到 miR-34a 增加 TASK-1 的表达和电流，并进一步降低表达 hTASK-1 的卵母细胞的静息膜电位。最后，我们研究了心房组织中 miRNA 表达与我们患者队列的临床参数之间的关联。一个包含 AF 阶段、左心室舒张末期直径、左心室收缩末期直径、左心房直径、心房 COL1A2（胶原 alpha-2(I) 链）和 TASK-1 蛋白水平的簇与 miR-25、miR-21、miR-34a、miR-23a、miR-124、miR-1 和 miR-29b 的表达增加以及 miR-9 和 miR-485 的表达减少相关。
这些结果表明，miRNA 在调节心房心肌病患者心房 TASK-1 钾通道表达方面具有重要的病理生理作用。
