Integrated analysis of microRNA and mRNA expression profiles in the left atrium of patients with nonvalvular paroxysmal atrial fibrillation: Role of miR-146b-5p in atrial fibrosis
Integrated analysis of microRNA and mRNA expression profiles in the left atrium of patients with nonvalvular paroxysmal atrial fibrillation: Role of miR-146b-5p in atrial fibrosis
复制标题
非瓣膜性阵发性心房颤动患者左心房 microRNA 和 mRNA 表达谱的综合分析：miR-146b-5p 在心房纤维化中的作用
DOI：
10.1016/j.hrthm.2015.01.026
复制
发表时间：
2015-05-01
期刊：
影响因子：
5.5
通讯作者：
Meng, Xu
中科院分区：
文献类型：
--
作者：
Wang, Jiangang;Wang, Yongyu;Meng, Xu
背景研究已经报道了microRNA（miRNA）-信使RNA（mRNA）的整合分析，本研究的目的是鉴定参与心房颤动的miRNA和基因，并探讨心房纤维化的机制。方法我们使用微阵列技术比较了10例房颤患者左心耳中miRNA和mRNA表达谱的差异。非瓣膜性阵发性房颤患者和健康对照组。同时，采用实时定量PCR技术验证微阵列数据的可靠性、数据库的预测性和miRNA-mRNA表达的不可逆性途径分析，以确定miRNA靶基因，研究靶基因参与的功能和途径，构建miRNA-靶基因调控网络。结果共鉴定出10个差异表达的miRNAs和624个差异表达的mRNAs，其中仅构建了1个miRNAs-靶基因对miR-146 b-5 p和组织金属蛋白酶抑制剂4（TIMP-4）。验证结果显示，在房颤患者中，miR-1466- 5 p、基质金属肽酶9和胶原含量上调，而TIMP-4下调。miR-146 b-5 p转染心肌成纤维细胞后，TIMP-4表达明显降低，胶原含量增加。结论miR-146 b-5 p可能通过调控TIMP-4的表达而调控心房纤颤的发生。miR-1466- 5 p可能是房颤心房纤维化适应不良重构的细胞内介质。
BACKGROUND Studies have reported that the integrated analysis of microRNA (miRNA)-messenger RNA (mRNA) expression is valuable in exploring gene regulation systemically.OBJECTIVES The objectives of this study were to identify miRNAs and genes involved in atrial fibrillation and to explore the mechanisms underlying atrial fibrosis.METHODS We used microarrays to compare the differences in both miRNA and mRNA expression profiles in the left atrial appendage of patients with nonvalvular paroxysmal atrial fibrillation and healthy controls. Furthermore, the quantitative real-time polymerase chain reaction was used to confirm the reliability of the microarray data, prediction of the adopted databases, and Ingenuity Pathway Analysis of miRNA-mRNA expression in order to identify the miRNA target genes, examine the functions and pathways in which the target genes are involved, and construct an miRNA-target gene regulatory network. We further investigated the roles of miRNA-146b-5p in the mechanisms of atrial fibrosis.RESULTS We identified 10 differentially expressed miRNAs and 624 differentially expressed mRNAs, among which only 1 miRNA-target gene pair miR-146b-5p and tissue inhibitor of metalloproteinase 4 (TIMP-4) were constructed. The validated results revealed that miR-1466-5p, matrix metallopeptidase 9, and collagen content were upregulated whereas TIMP-4 was downregulated in patients with atrial fibrillation. After the transfection of miR-146b-5p into cardiac fibroblasts, TIMP-4 expression was markedly reduced and collagen content was increased. Moreover, Luciferase results confirmed that TIMP-4 was a target of miR-146b-5p.CONCLUSION The identified miRNA and mRNA may represent a potentially novel molecular regulatory network, which may provide a better understanding of the molecular basis of remodeling in atrial fibrillation. miR-1466-5p probably acts as an intracellular mediator in the maladaptive remodeling in atrial fibrosis in atrial fibrillation.