低氧下调miR-223在肺动脉高压形成中的作用及分子机制研究

肺动脉高压的发病机制复杂，死亡率高。多认为肺动脉平滑肌细胞(PASMC)异常增殖和肺血管结构重建是低氧性肺动脉高压(HPH)的重要特征。前期研究表明，低氧使miR-223在PASMC和小鼠肺组织表达下调，而RhoB蛋白则上调；且RhoB是miR-223的靶基因；在功能上，miR-223抑制PASMC增殖。本项目推测，miR-223通过RhoB参与的Rho/Rho激酶信号通路调控HPH的发生。为了验证该假设，拟从细胞水平研究miR-223对Rho/Rho激酶通路的调控，及在此基础上引起的PASMC增殖、迁移等变化；以HPH大鼠为模型，探讨miR-223喷剂对HPH症状的改善作用；最后通过PAH患者样本分析，明确miR-223与PAH在临床上的关系。本项目不仅有助于从miRNA调控Rho/Rho激酶通路的角度阐明HPH的分子机理，还能为开发基于miRNA的治疗和早期诊断手段提供新思路。

Pulmonary arterial hypertension (PAH) is a complex vascular disease with a dreadful survival rate. Hypoxia-induced pulmonary arterial hypertension (HPH) is characterized by abnormal proliferation of pulmonary artery smooth muscle cell (PASMC) and progressive structural remodeling of pulmonary arteries. Our preliminary data showed that miR-223 was remarkably down-regulated in hypoxia-treated PASMC and lung tissues, and RhoB, a member of Rho/Rho kinase pathway, was significantly up-regulated by hypoxia. Further studies confirmed that RhoB is a direct target of miR-223. Functionally, miR-223 inhibits the proliferation of PAMSC. Based on the results above, we propose that the development of HPH might be associated by miR-223 through the regulation of Rho/Rho kinase pathway. In this proposal, the targeting of Rho/Rho kinase pathway by miR-223, as well as its influence upon proliferation and migration of PASMC will be explored. Using hypoxia induced HPH rat model, the impact of synthetic miR-223 sprays on pulmonary vascular remodeling and HPH symptoms will be investigated. Finally, the clinical relationship between miR-223 level and PAH disease will be evaluated. The purpose of this project is to elucidate the molecular mechanism of HPH regulated by miR-223 via Rho/Rho kinase pathway and might provide a new clue for the development of miRNA-based treatment and early diagnostics means for HPH.