lncRNA NAV2-AS2调节EndMT与FMT抗尼古丁致心肌纤维化的作用机制研究

烟草主要成分尼古丁可诱发心肌纤维化，明晰尼古丁作用于心脏的关键靶点是研究的瓶颈问题。芯片结果显示lncRNA NAV2-AS2在尼古丁刺激的小鼠心脏组织中低表达，对尼古丁刺激的小鼠过表达NAV2-AS2后，心肌纤维化得到明显改善。KEGG分析显示，NAV2-AS2过表达后，冠脉内皮细胞中内皮间质转化（EndMT）相关通路及心脏成纤维细胞中Apelin信号通路发生最明显改变，Apelin为成纤维向肌成纤维转化（FMT）的抑制因子。基于以上内容我们建立如下科研假设：（1）尼古丁作用下，NAV2-AS2表达降低，从而通过“互补稳定”机制下调NAV2表达，减弱其与Snail复合体的结合抑制作用，诱导EndMT，导致心肌纤维化。（2）NAV2-AS2表达下降使得miR-182升高，继而抑制Apelin表达，导致FMT，诱发心肌纤维化。本研究揭示了尼古丁致心肌纤维化的新机制，提供了可行的药物靶点。

Nicotine, one of the main constituents of tobacco, could induce myocardial fibrosis. Clearing the key regulatory molecules of nicotine in hearts is the bottleneck of research. We performed lncRNA gene chip analysis, and found that lncRNA NAV2-AS2 was significantly down-regulated in nicotine-treated cardiac tissue. Overexpression of NAV2-AS2 in nicotine-treated mice showed significant improvement in myocardial fibrosis. KEGG analysis demonstrated that overexpression of NAV2-AS2 significantly influenced the endothelial to mesenchymal transition (EndMT)-related pathway in coronary artery endothelial cells and Apelin pathway in cardiac fibroblasts. Apelin is an inhibitor of fibroblast to myofibroblasts transition (FMT). Based on the above, we have established the following scientific hypothesis: (1) Nicotine treatment decreases NAV2-AS2 expression, and then the expression of sense-gene NAV2 is down-regulated by the "complementary stability" mechanism, further attenuating its inhibitory effect on Snail complex, inducing EndMT and myocardial fibrosis. (2) At the same time, down-regulation of NAV2-AS2 results in an increase in miR-182, which leads to Apelin inhibition and FMT, which in turn leads to myocardial fibrosis. Our research revealed new mechanisms and provided effective drug targets for nicotine-induced myocardial fibrosis.