MALAT1与 miR-146a相互作用对 EndMT及心肌纤维化的影响及其机制研究

Endothlial-mesenchymal transition, EndMT promotes cardic fibrosis (CF). Smad2, Smad3 and Smad4, which are the effector molecular of TGF-β signaling pathway in the process of EndMT, are the key proteins during EndMT in CF. lncRNA MALAT1 and miR-146a highly express in endothelial cells and play an important role in endothelial functions. MALAT1 promotes epithelial-mesenchymal transition, which share similar mechanisms of EndMT, and miR-146a has been proven to play a protective role in mesenchymal transition, inhibit Smad2/3/4 and improve collagen metabolism. Relationship among MALAT1, miR-146a and EndMT are unknown. Our pre-experiment showed that MALAT1 promoted EndMT and miR-146a inhibited this process. Moreover, MALAT1 and miR-146a have a reversely expression pattern. The "Starbase" predictive formula show a binding structure between MALAT1 and miR-146a and a possibility that MALAT1 and miR-146a inhibit each other. Therefore, we aim to demonstrate the effects of MALAT1 in the EndMT and CF, and elucidate the roles of miR-146a and Smad2/3/4 in this process using human aortic endothelial cells and Tie2-lacZ mice, which facilitate endothelium tracking. Besides, we sought to explore the regulatory effects between MALAT1 and miR-146a. Our program will provide more mechanisms of EndMT and CF, which might give more information in clinical practice.

内皮间质转化（EndMT）是促进心肌纤维化（CF）的重要因素。Smad2/3/4是介导CF中EndMT的关键蛋白。MALAT1和miR-146a是高表达于内皮细胞的非编码RNA。前者可促进上皮-间质转化及内皮细胞迁移而后者则被证实可抑制间质细胞表型转变、抑制Smad2/3/4并改善胶原代谢，但两者与EndMT关系均不清楚。我们前期研究发现，MALAT1促进EndMT而miR-146a则抑制EndMT，且两者在内皮细胞呈反向表达。生物信息学分析显示两者可能相互结合并彼此抑制。因此，本研究使用人主动脉内皮细胞和内皮示踪转基因小鼠，明确MALAT1和miR-146a在EndMT中的作用；通过上调或下调miR-146a及Smad2/3/4证实两者在介导MALAT1促EndMT中的作用。并通过一系列方法阐明MALAT1与miR-146a交互作用的机制，为CF的防治提供新的思路和理论依据。

心肌纤维化是心力衰竭和心室重构的最重要病理改变，也是心力衰竭治疗的重要靶点。心肌成纤维细胞活化是心肌纤维化发生和持续进展最主要的驱动因素。对心肌成纤维细胞活化机制进行的研究是心肌纤维化研究领域的热点。长期以来，已有许多研究人员针对编码基因调控心肌纤维化机制展开研究，但非编码RNA调控心肌纤维化的报导尚不多见。本项目立足于非编码RNA与心肌纤维化的关系研究，探讨了非编码RNA参与人心脏成纤维细胞活化的病理生理机制研究。该项目不仅发现了长非编码RNA Linc00092通过调控糖酵解参与心脏成纤维细胞活化过程，还发现了小非编码RNA miR-10b-5p通过外泌体包裹进入成纤维细胞参与集落形成细胞对成纤维细胞活化的抑制作用。本项目为非编码RNA参与心肌纤维化调控提供了基础实验证据的补充，为利用非编码RNA调控心脏成纤维细胞进而干预心肌纤维化的可能提供了理论参考。