miR-124在实验性肺动脉高压中的作用及其机制研究

Pulmonary arterial hypertension (PAH), a severe disease with high mortality, is lack of effective treatment currently. The pathogenesis of PAH has not been elucidated. Studies show that the proliferation, migration and pro-inflammation of vascular adventitial fibroblasts play important roles in the process of vascular remodeling and PAH. MiR-124 could not only regulate the proliferation, migration and inflammatory phenotypic differentiation of pulmonary adventitial fibroblasts，but also inhibit the proliferation of vascular smooth muscle cells. Our preliminary experiments showed that overexpression of miR-124 markedly ameliorated pulmonary hypertension induced by hypoxia, and reduced the extent of reconstruction of small arteries in the lungs of rats obviously. In the present study, we will investigate the effects of over-expression of miR-124 mediated by lentivirus in the models of PAH induced by hypoxia and monocrotaline, respectively, and will explore the possible mechanism in vivo and in vitro. The results may reveal the pathogenesis of PAH and find new therapeutic targets of PAH.

肺动脉高压（PAH）死亡率高、发病机制未明，目前缺乏有效治疗手段。研究表明：血管外膜成纤维细胞的增殖、移行和促炎反应在肺血管重建和PAH形成中发挥重要的作用；miR-124具有调控肺动脉外膜成纤维细胞的增殖、移行及炎性表型分化，抑制血管平滑肌细胞增殖的作用。我们的初步试验结果显示，过表达miR-124不仅能够明显降低缺氧诱导的大鼠肺动脉高压，而且能减轻肺内小动脉的重建。本研究将采用慢病毒介导的miR-124基因导入的方法，分别在缺氧和野百合碱诱导的大鼠PAH模型中，深入研究过表达miR-124对PAH的干预效应，并在整体和细胞水平上探讨其可能的作用机制，为解析PAH的发病机理和寻找新的治疗靶点提供思路。

肺动脉高压(PAH)是一种死亡率高、预后极差的严重肺血管疾病。肺动脉血管平滑肌细胞和外膜成纤维细胞的异常增殖诱导的肺血管重构是导致肺血管阻力进行性升高的主要原因。既往的体外研究表明：miR-124对肺血管平滑肌细胞和血管外膜成纤维细胞的增殖有明显的抑制作用。本项目通过重组腺相关病毒载体介导的miR-124过表达的方法，探讨miR-124对野百合碱诱导的大鼠肺动脉高压的作用并对其可能机制进行了初步探讨。首先构建miR-124腺相关病毒表达载体，大量包装目标病毒和对照病毒，将其浓缩纯化后干预野百合碱诱导的大鼠肺动脉高压模型，检测大鼠血流动力学、右心肥厚指数、组织形态学等相关指标，并检测TNF-α、TGF-β1等炎性因子及IL-6/STAT3、TGF-β1、PDGFR等信号通路分子的表达。研究结果表明：miR-124过表达可显著降低野百合碱诱导的大鼠右心室收缩压、右心肥厚程度、并减轻肺血管重构；其作用机制可能与miR-124调节IL-6/PDGF/TGF-β1-STAT3信号通路有关。该研究的结果为肺动脉高压的治疗提供新的思路，为开发新的治疗肺动脉高压的药物以及基因治疗的实施提供了证据，但是其具体机制仍需要进一步深入研究。