Department of Cardiology, The Second Hospital of Hebei Medical University, 215 West Heping Road, Shijiazhuang, 050000, Hebei, People's Republic of China.
Department of Geriatrics, Hebei General Hospital, Shijiazhuang, 050051, Hebei, People's Republic of China.
Mol Biol Rep. 2020 Apr;47(4):2605-2617. doi: 10.1007/s11033-020-05347-0. Epub 2020 Mar 4.
Atrial fibrillation (AF) is a commonly encountered heart arrhythmia and a risk factor for cardiovascular system. The purpose of the present study was to explore the role of long non-coding RNA myocardial infarction-associated transcript (MIAT) in AF and AF-induced myocardial fibrosis and the possible mechanisms involved in this process. We successfully induced an AF rat model. Expression of MIAT presented a dramatic increase, while microRNA (miR)-133a-3p presented a dramatic decrease in atrium tissues of rats with AF induction. In addition, we also found that MIAT was highly expressed and miR-133a-3p was significantly reduced in peripheral blood leukocyte of AF patients. For biological function exploration of MIAT/miR-133a-3p axis, MIAT was knocked down using small hairpin RNA (shRNA) lentivirus injection and the rescue experiments were performed simultaneously by inhibiting miR-133a-3p using anti-miR-133a-3p lentivirus injection in rats with AF. MIAT downregulation significantly alleviated AF, increased atrial effective refractory period (AERP), and reduced the duration of AF as well as cardiomyocytes apoptosis. Whereas these effects of MIAT downregulation on AF were reversed by anti-miR-133a-3p administration. Luciferase reporter revealed that miR-133a-3p was directly regulated by MIAT. Moreover, MIAT knockdown effectively reduced AF-induced atrial fibrosis by detecting reduced collagen in the right atria and inhibited expression of fibrosis-related gene expression of collagen I, collagen III, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1) in rats with AF, these findings were in contrast with the findings for rats with inhibition of miR-133a-3p. In conclusion, our study demonstrated the role of MIAT downregulation in alleviating AF and AF-induced myocardial fibrosis, and the functional regulatory pathway of MIAT targeting miR-133a-3p.
心房颤动（AF）是一种常见的心律失常，也是心血管系统的危险因素。本研究旨在探讨长链非编码 RNA 心肌梗死相关转录物（MIAT）在 AF 及 AF 诱导的心肌纤维化中的作用及其可能的作用机制。我们成功地建立了 AF 大鼠模型。在 AF 大鼠的心房组织中，MIAT 的表达明显增加，而 microRNA（miR）-133a-3p 的表达明显降低。此外，我们还发现 MIAT 在 AF 患者的外周血白细胞中高表达，而 miR-133a-3p 则显著降低。为了探讨 MIAT/miR-133a-3p 轴的生物学功能，我们采用小发夹 RNA（shRNA）慢病毒注射法下调 MIAT，并用抗 miR-133a-3p 慢病毒注射抑制 miR-133a-3p 进行同时的挽救实验。在 AF 大鼠中，下调 MIAT 可显著减轻 AF，增加心房有效不应期（AERP），缩短 AF 持续时间及减少心肌细胞凋亡。而 MIAT 下调对 AF 的这些作用可被抗 miR-133a-3p 给药逆转。荧光素酶报告基因显示，miR-133a-3p 可直接被 MIAT 调控。此外，通过检测右心房胶原含量的减少，以及抑制纤维化相关基因胶原 I、胶原 III、结缔组织生长因子（CTGF）和转化生长因子-β1（TGF-β1）在 AF 大鼠中的表达，证实了 MIAT 下调可有效减轻 AF 诱导的心房纤维化，这与抑制 miR-133a-3p 的大鼠结果相反。综上所述，本研究表明 MIAT 下调可缓解 AF 及 AF 诱导的心肌纤维化，并阐明了 MIAT 通过靶向 miR-133a-3p 发挥功能调节作用的途径。
