miR-451a上调在缺氧性肺动脉高压形成中的作用及分子机制

Pulmonary arterial hypertension (PAH) is a complicated vascular disease, and hypoxia pulmonary arterial hypertension (HPH) is characterized by abnormal proliferation of pulmonary artery smooth muscle cell (PASMC) and pulmonary vascular structural remolding. According to preliminary miRNA profiling in human pulmonary artery smooth muscle cell (HPASMC), we found that the expression of miR-451a was significantly up-regulated by hypoxia inducing; and circulating miR-451a in serum was also significantly up-regulated. Moreover, we observed miR-451a is functionally associated with HPASMC proliferation, and TSC1 is a direct target gene of miR-451a. Based on these results, we hypothesize that miR-451a might involve inPI3K/AKT/mTOR pathway via TSC1 and take part in the development of PAH by hypoxia inducing. In this proposal, we will further investigate: 1)the biological functions of miR-451a in hypoxia related PASMC poliferation and PAH development; 2) the molecular mechenism of hypoxia induced up-regulation of miR-451a; 3) the impact of synthetic miR-451a on PAH symtoms in hypoxia induced rat model; 4) the relationship between miR-451a and the development of different kinds of PAH in clinic. Overall, by integrating the findings from in vitro, in vivo and clinical levels, this project will precisely reveal the functions and mechanisms of miR-451a in hypoxia induced PAH, aiming to find new cues for studying the pathogenesis of PAH and new PAH therapeutic targets.

肺动脉高压(PAH)发病机制复杂，肺动脉平滑肌细胞(PASMC)异常增殖和肺血管结构重建是缺氧性肺动脉高压（HPH）的重要特征。前期研究表明：缺氧使miR-451a在人肺动脉平滑肌细胞中表达上调；先心病合并肺高压病人血清中miR-451a表达也上调；功能上miR-451a促进PASMC增殖且预测其靶基因是TSC1。根据前期结果推测，miR-451a通过TSC1参与的PI3K/AKT/mTOR激酶信号通路调控HPH的发生。基于此，本项目将深入研究：1) miR-451a在PASMC中的功能及作用机制；2)缺氧上调miR-451a表达的分子机理；3)大鼠模型中抑制miR-451a对PAH症状的改善作用；4）miR-451a与PAH在临床上的关系。本项目结合细胞、动物及临床数据，旨在揭示miR-451a在PAH形成中的功能及作用机制，为解析PAH的发病机理和寻找新的治疗靶点提供新思路。

肺动脉高压(PAH)发病机制复杂，死亡率高。肺血管重构是PAH重要的病理学基础，基因突变是其发生最根本的原因。项目执行期间发现，miR-451a在肺动脉平滑肌细胞中具有功能，且miR-451a的靶基因是TSC1。在低氧或者野百合碱（MCT）诱导的PAH大鼠肺动脉中， miR-451a显著下调（分别下调约70%和65%），miR-451a敲除小鼠可回复缺氧引起的肺动脉压力升高和血管壁重构，但是无法回复右心室肥厚指数，揭示miR-451a表达紊乱与肺动脉高压和右心室衰竭密切相关。项目期间还发现miR-451a在肺动脉成纤维细胞中特异性高表达，在中层平滑肌细胞和内层内皮细胞中表达水平相对较低。miR-451a可以促进成纤维细胞增殖和迁移，并且在缺氧大鼠肺动脉外膜（成纤维细胞）中显著上调（约3.5倍）。结论：miR-451a在肺动脉高压中具有重要作用，但是在不同的肺动脉细胞中可能发挥不同的功能。miR-451a敲除鼠在缺氧条件下肺动脉压力正常，但是右心室肥厚指数较高，有望建立一种新的右心室衰竭的动物模型。