Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation
Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation
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DOI：
10.1016/j.hrthm.2009.08.035
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发表时间：
2009-12-01
期刊：
影响因子：
5.5
通讯作者：
Ehrlich, Joachim R.
中科院分区：
文献类型：
--
作者：
Girmatsion, Zenawit;Biliczki, Peter;Ehrlich, Joachim R.
心房颤动（AF）与增加的内向整流电流活动有关，内向整流电流活动可以稳定心房转子，维持心律失常。左心房（LA）结构对于AF维持很重要，但以前的研究主要评价右心房的变化。microRNA-1（miR-1）介导内向整流钾通道（Kir）2.1在冠心病中的表达，促进心肌梗死的发生。本研究旨在评估miR-1和Kir 2亚基表达的变化与持续性AF患者LA IK 1改变的关系。从分离的细胞记录电流。从免疫印迹定量蛋白质。用实时聚合酶链反应测定mRNA和miR-1水平。结果房颤患者心房肌细胞IK 1表达增加（-100 mV时：-5.9 +/-1.3 vs. -2.7 +/-0.7，P <0.05）; Kir2.1蛋白表达相应增加，但其他Kir或Cx蛋白无变化。在AF患者的组织样本中，抑制性miR-1的表达减少了约86%。Kir2.1 mRNA表达显著增加。Cx43定位未发生变化。体外快速刺激人心房切片上调Kir 2. 1和下调miR-1，提示心房率在miR-1下调和IK 1上调中起主要作用。结论miR-1在人AF中水平显著降低，可能与Kir 2. 1亚基上调有关，导致IK 1增加。由于内向整流电流的上调对房颤的维持很重要，这些结果为房颤的分子机制提供了潜在的新见解，具有潜在的治疗意义。
BACKGROUND Atrial fibrillation (AF) is associated with increased inward-rectifier current activity that may stabilize atrial rotors maintaining the arrhythmia. Left atrial (LA) structures are important for AF maintenance, but previous studies have mostly evaluated changes in the right atrium. MicroRNA-1 (miR-1) reciprocally regulates inwardly rectifying potassium channel (Kir)2.1 expression in coronary disease, contributing to arrhythmogenesis.OBJECTIVES This study sought to evaluate changes in miR-1 and Kir2 subunit expression in relation to IK1 alterations in LA of patients with persistent AF.METHODS Atrial tissue was obtained from 62 patients (31 with AF) undergoing mitral valve repair or bypass grafting. Currents were recorded from isolated cells. Proteins were quantified from immunoblots. mRNA and miR-1 levels were measured with real-time polymerase chain reaction. Immunohistochemistry was applied to localize connexin (Cx) 43.RESULTS IK1 density was increased in LA cells from patients with AF (at -100 mV: -5.9 +/- 1.3 vs. -2.7 +/- 0.7 sinus rhythm, P < .05). There was a corresponding increase in Kir2.1 protein expression, but no change in other Kir or Cx proteins. Expression of inhibitory miR-1 was reduced by approximately 86% in tissue samples of AF patients. Kir2.1 mRNA was significantly increased. No change in Cx43 localization occurred. Ex vivo tachystimulation of human atrial slices up-regulated Kir2.1 and down-regulated miR-1, suggesting a primary role of atrial rate in miR-1 downregulation and IK1 up-regulation.CONCLUSION miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased IK1. Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.