Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C
Inhibiting microRNA-155 attenuates atrial fibrillation by targeting CACNA1C
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抑制 microRNA-155 通过靶向 CACNA1C 减轻心房颤动
DOI：
10.1016/j.yjmcc.2021.02.008
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发表时间：
2021-03-05
影响因子：
5
通讯作者：
Ma, Yue
中科院分区：
文献类型：
--
作者：
Wang, Jiangang;Ye, Qing;Ma, Yue
背景：心房颤动（AF）时，L型钙电流（I-Ca，I-L）密度降低是电重构的标志。在阵发性房颤患者的心房肌细胞（aCMs）中，miR-155的表达上调，其预测的靶基因是钙通道α 1c亚基（CACNA 1C），本研究旨在确定miR-155是否能够靶向I-Ca、I-L的基因表达，并参与房颤的电重构。评估了来自阵发性AF患者和健康对照的aCM中miR-155和CACNA 1C的表达。在人诱导多能干细胞衍生的心房心肌细胞（hiPSC-aCM）中转染miR-155后观察I-Ca、I-L特性。此外，通过靶向CACNA 1C，产生miR-155转基因（Tg）和敲除（KO）小鼠模型以确定miR-155是否参与AF中I-Ca、I-L相关的电重构。miR-155在AF患者aCM中的表达水平增加，而CACNA 1C的表达水平降低。miR-155转染hiPSC-aCM引起I-Ca的变化，I-L性质定性上类似于AF产生的I-L性质。miR-155/Tg小鼠出现了缩短的动作电位持续时间和增加的AF易感性，这与I-Ca、I-L降低相关，并被miR-155抑制剂减弱。最后，在miR-155/KO小鼠中，miR-155的基因抑制阻止了AF的诱导，而I-Ca、I-L特性没有变化。结论：aCMs中miR-155表达的增加足以降低I-Ca、I-L密度和潜在的电子重构。抑制miR-155可抑制房颤中I-Ca、I-L相关的电重构，可能成为一种以电重构为靶点的抗房颤新途径。
Background: Reduction in L-type Ca2+ current (I-Ca,I-L) density is a hallmark of the electrical remodeling in atrial fibrillation (AF). The expression of miR-155, whose predicted target gene is the alpha 1c subunit of the calcium channel (CACNA1C), was upregulated in atrial cardiomyocytes (aCMs) from patients with paroxysmal AF.The study is to determine miR-155 could target the gene expression of I-Ca,I-L and contribute to electrical remodeling in AF.Methods: The expression of miR-155 and CACNA1C was assessed in aCMs from patients with paroxysmal AF and healthy control. I-Ca,I-L properties were observed after miR-155 transfection in human induced pluripotent stem cell derived atrial cardiomyocytes (hiPSC-aCMs). Furthermore, an miR-155 transgene (Tg) and knock-out (KO) mouse model was generated to determine whether miR-155 was involved in I-Ca,I-L-related electrical remodeling in AF by targeting CACNA1C.Results: The expression level of miR-155 was increased, while the expression level of CACNA1C reduced in the aCMs of patients with AF. miR-155 transfection in hiPSC-aCMs produced changes in I-Ca,I-L properties qualitatively similar to those produced by AF. miR-155/Tg mice developed a shortened action potential duration and increased vulnerability to AF, which was associated with decreased I-Ca,I-L and attenuated by an miR-155 inhibitor. Finally, the genetic inhibition of miR-155 prevented AF induction in miR-155/KO mice with no changes in I-Ca,I-L properties.Conclusions: The increased miR-155 expression in aCMs was sufficient for the reduction in the density of I-Ca,I-L and the underlying electronic remodeling. The inhibition of miR-155 prevented I-Ca,I-L-related electric remodeling in AF and might constitute a novel anti-AF approach targeting electrical remodeling.