微小RNA-222在运动防治肺动脉高压所致肺血管重构中的作用及机制研究

我们先前发表于Cell Metabolism杂志的研究表明，微小RNA-222（miR-222）是一个运动保护心血管的关键微小RNA。进一步发现，miR-222在运动后的肺组织下调，而在野百合碱诱导的肺动脉高压（PAH）模型内上调，过表达miR-222可在体外促进肺动脉平滑肌细胞增殖。运动被报道可以改善PAH所致肺血管重构，提示运动也许可以通过下调miR-222防治PAH所致肺血管重构。本项目拟在动物水平（野百合碱和缺氧诱导PAH，基因工程大鼠或气道注射腺相关病毒干预miR-222）和细胞水平（肺血管内皮细胞、平滑肌细胞和成纤维细胞），明确miR-222和运动防治PAH所致肺血管重构的关系。随后，基于靶基因p27、Hmbox1、HIPK1、HIPK2和TIMP3进行功能挽救实验，阐明miR-222介导运动防治PAH所致肺血管重构的分子基础。本项目将为PAH所致肺血管重构的治疗提供新靶点。

We previously reported in Cell Metabolism that microRNA-222 (miR-222) is a key regulator contributing to the benefit of exercise in cardiovascular function. Furthermore, we found that miR-222 was significantly downregulated in lung tissues in response to exercise, while upregulated in monocrotaline-induced pulmonary arterial hypertension (PAH). Overexpression of miR-222 could enhance the proliferation of pulmonary arterial smooth muscle cells in vitro. Exercise has been reported to be beneficial for PAH and vascular remodeling. These data suggest that exercise might be able to protect against PAH and vascular remodeling via downregulating miR-222..In this project, we will firstly, based on in vivo (monocrotaline- and hypoxia-induced PAH animal models, using genetic engineering rats or intratracheal injection of adeno-associated virus to regulate miR-222 expression level) and in vitro (pulmonary arterial endothelial cells, smooth muscle cells, and fibroblasts) experiments, clarify the roles of miR-222 in the benefit of exercise in PAH and vascular remodeling. Secondly, based on our previously identified target genes including p27, Hmbox1, HIPK1 and HIPK2, and novel identified target gene TIMP3, we will perform function-rescue assays to elucidate the downstream molecular mechanisms mediating the roles of miR-222 in the benefit of exercise in PAH and vascular remodeling. Our project will identify a novel therapeutic target for PAH and vascular remodeling.