最近认为除PASMCs增殖外，内皮间质转化（EndMT）也是肺动脉高压（PH）血管重构的重要因素。前期我们发现let-7g可抑制PASMCs增殖，然而，其在EndMT中的作用尚无报道。预实验我们通过生物信息学技术发现let-7g与PH时EndMT关系密切；大鼠低氧可下调肺动脉let-7g表达，同时诱导EndMT；肺动脉内皮细胞过表达let-7g能显著抑制低氧诱导的EndMT；lncRNA-H19在低氧大鼠肺动脉中上调且与let-7g靶向结合。据此，我们推测H19/let-7g轴可抑制低氧PH时EndMT。本项目拟通过在体动物与细胞实验相结合，阐明H19/let-7g轴抑制PH时EndMT的作用，并探讨潜在的上游机制（HIF-1α/H19/let-7g通路）及下游机制（let-7g/TGFβRⅠ/Smads/snail通路）。本项目将有助于阐明PH的发病机制，为寻找防治PH的新靶点奠定基础。

Pulmonary hypertension (PH) is characterized by hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) within the vascular wall of resistant pulmonary arteries, leading to vascular lumen occlusion. Recent studies found that not only PASMCs proliferation but also endothelial-mesenchymal transition (EndMT) was the key factor leading to vascular remodeling. Our group found let-7g can inhibited hypoxia-induced PASMCs proliferation. However, the role of let-7g in EndMT remains unknown. Our pilot study for the first time found let-7g associated with EndMT during vascular remodeling in PH by a network-based bioinformatics approach. The expression of let-7g was downregulated in hypoxia-induced PH rats and pulmonary artery endothelial cells (PAECs), and EndMT marker proteins (α-SMA and CD31) were significantly up-regulated in the pulmonary artery intima of hypoxic-induced PH rats, lncRNA-H19 was upregulated in hypoxia-induced PH rats and can targeted let-7g, which implied that H19let-7g axis may suppress EndMT during PH. We will be planning to explore the important potential role of H19/let-7g axis in the EndMT during pulmonary vascular remodeling in PH rats and cultured PAECs. Furthermore, we will investigate the underlying mechanisms responsible for the down-regulation of let-7g in pulmonary artery intima in hypoxia-induced PH rats (focusing on HIF-1α/H19/let-7g) and the downstream signaling that let-7 inhibits EndMT (focusing on let-7g/TGFβRⅠ/Smads/snail). This study will contribute to the understanding of pathogenesis of PH, and provide new strategies to seek for the new drugs directing at let-7 targe may regulate multiple disease pathways in the pulmonary vasculature, but their importance in PH is just beginning to emerge.