Department of Cardiovascular Medicine, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China.
Department of Cardiovascular Medicine, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, China.
J Cell Biochem. 2018 Dec;119(12):10239-10249. doi: 10.1002/jcb.27366. Epub 2018 Aug 26.
The dysregulation of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) participates in the remodeling of electrophysiological/ion channel in cardiomyocytes during arrhythmia. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is reported to be highly expressed in myocardial ischemia-reperfusion injury and offsets cardioprotective effects of fentanyl. However, the roles of MALAT1 and its related miRNAs during arrhythmia are poorly understood. In this study, the overexpression of MALAT1 was firstly indicated in cardiomyocytes from arrhythmic model rats. After downregulation of MALAT1 by RNA interference, transient outward potassium current (Ito), peak current density, and the levels of Kv4.2 and Kv4.3 channel proteins were increased in rat cardiomyocytes. Then, miR-200c was predicted and convinced to be a direct target of MALAT1, and high-mobility group box 1 (HMGB1) was verified to be a target of miR-200c during arrhythmia. HMGB1 expression reduced by the knockdown of MALAT1 was further decreased by miR-200c overexpression. In addition, cardiac Ito, peak current density, and the levels of Kv4.2 and Kv4.3 in arrhythmic model rats were detected to be negatively correlated with the expression of HMGB1, and to be positively with miR-200c expression. Taken together, these results suggested that MALAT1 may act as a competing endogenous RNA for miR-200c to upregulate the expression of HMGB1 and downregulate cardiac Ito.
长链非编码 RNA（lncRNA）和 microRNA（miRNA）的失调参与心律失常中心肌细胞电生理/离子通道的重构。据报道，转移相关肺腺癌转录本 1（MALAT1）在心肌缺血再灌注损伤中表达水平较高，抵消了芬太尼的心脏保护作用。然而，MALAT1 及其相关 miRNA 在心律失常中的作用知之甚少。在这项研究中，首先在心律失常模型大鼠的心肌细胞中表明 MALAT1 过表达。通过 RNA 干扰下调 MALAT1 后，大鼠心肌细胞中的瞬时外向钾电流（Ito）、峰值电流密度以及 Kv4.2 和 Kv4.3 通道蛋白水平升高。然后，预测并证实 miR-200c 是 MALAT1 的直接靶标，并且高迁移率族蛋白 B1（HMGB1）在心律失常期间被证实是 miR-200c 的靶标。通过下调 MALAT1 减少的 HMGB1 表达进一步被 miR-200c 过表达所降低。此外，在心律失常模型大鼠中检测到心脏 Ito、峰值电流密度以及 Kv4.2 和 Kv4.3 水平与 HMGB1 的表达呈负相关，与 miR-200c 的表达呈正相关。总之，这些结果表明，MALAT1 可能作为 miR-200c 的竞争性内源 RNA，上调 HMGB1 的表达并下调心脏 Ito。
