LncRNA TUG1在肺动脉平滑肌细胞增殖和肺血管重构中的作用及机制研究

Pulmonary arterial hypertension is a malignant cardiovascular disease, which mechanisms are still poorly understood. Long non-coding RNAs (lncRNAs) have critical roles in diverse biological processes，including proliferation and apoptosis. However, the biological role of lncRNA in pulmonary arterial hypertension remains unknown. We have found that the expression of lncRNA TUG1 showed significant increase in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension and in the lungs of patients with pulmonary arterial hypertension. Moreover, TUG1 induced human PASMC proliferation and inhibited PASMC apoptosis. All these data indicates that TUG1 may play an important role in pulmonary vascular remodeling and pulmonary arterial hypertension. To address these issues, we will carry out our studies as follows: 1. Examining the levels and location of TUG1 in pulmonary arterial hypertension. 2. Exploring the roles of TUG1 in pulmonary vascular remodeling. 3. Determining the target and the interaction network of TUG1 in pulmonary arterial hypertension. Taken together, we will establish for the first time that TUG1 plays an important role in pulmonary vascular remodeling, which might be valuable in the future for treating and preventing pulmonary arterial hypertension.

肺动脉高压是一种恶性程度极高的心血管疾病，发病机制尚未明确。长链非编码 RNA (lncRNA) 可参与与细胞增殖、凋亡等相关的诸多环节，从而发挥其在疾病进程中的关键作用。但lncRNA在肺动脉高压中的作用及分子机制尚不清楚。我们发现，lncRNA TUG1在肺动脉高压大鼠模型及肺动脉高压患者肺组织中的表达均明显上调；TUG1还可调控肺动脉平滑肌细胞的增殖及凋亡，提示TUG1可能通过调控肺血管重构引起肺动脉高压。拟通过下述研究证明该假设：1、揭示肺动脉高压中TUG1的表达及分布变化特点。2、阐明TUG1在肺血管重构中的作用及机理。3、确定参与TUG1调控肺动脉平滑肌细胞增殖、凋亡的靶点及其相互作用的网络。本申请首次阐明lncRNA TUG1在肺动脉高压中的作用机制，为揭示该病的发病机理及靶点治疗提供了新的理论依据。

《LncRNA TUG1在肺动脉平滑肌细胞增殖和肺血管重构中的作用及机制研究》课题获得国家自然科学基金资助，课题负责人王爽，现已达到研究预期目标，研究内容已全部完成，发表SCI论文2篇，均发表在国外有影响的杂志上。在本项目资助下发现：1.在肺动脉高压动物模型及肺动脉高压患者中，TUG1的表达量均上调，TUG1定位于肺动脉平滑肌细胞质和细胞核中，且在缺氧时表达增加；2.抑制肺动脉高压小鼠TUG1的表达后，肺血管重构及右心室压升高有所缓解，且TUG1可通过调控肺动脉平滑肌细胞周期促进细胞增殖，及抑制肺动脉平滑肌细胞的凋亡；3.TUG1通过作用于miR-328及其下游的靶蛋白IGF-1R等，发挥其在肺动脉平滑肌细胞增殖中的作用。以上研究结果证实TUG1在肺动脉肺动脉平滑肌细胞增殖和肺血管重构中的作用，发现了TUG1参与肺动脉高压发病的新机制，为实现肺动脉高压的基因治疗提供了一个新的具有应用前景的靶点。