肺高压（pulmonary hypertension，PH）时肺动脉阻力增加的主要病因是肺血管重构导致肺动脉腔隙狭窄。近期有学者运用miRNAs网络药理学发现let-7家族与TGF-β、低氧及炎症诱导的PH关系密切。然而，let-7家族在PH中的作用还未见文献报道。我们的预实验发现，let-7家族中let-7b/g在低氧诱导的PH大鼠肺动脉中表达下调，let-7g mimic能显著抑制低氧诱导的原代大鼠肺动脉平滑肌细胞增殖，因此我们推测let-7家族参与低氧诱导PH肺血管重构。本项目拟通过在体动物与细胞实验相结合，探讨低氧PH发病过程中let-7下调的机制（HIF-1α/PKC/ERK1/2/c-myc/let-7正反馈调节）及let-7抑制肺血管重构的机制（let-7/RAS/c-myc/bmi-1/p16）。本项目将有助于阐明PH的发病机制，为寻找防治PH的新靶点奠定实验和理论基础。

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 microRNAs may regulate multiple disease pathways in the pulmonary vasculature, but their importance in PH is just beginning to emerge. Further, researchers identified miRNAs associated with multiple pathogenic pathways (TGF-β, hypoxia and inflammation) central to PH which including let-7 by a network-based bioinformatics approach. However, the role of let-7 in pulmonary vascular remodeling in pulmonary hypertension remains unknown. Our pilot study showed that the expression of let-7b/g was downregulated in hypoxia-induced PH rats, and the let-7g mimic significantly inhibited proliferation of primary cultured PASMCs induced by hypoxia. We will be planning to explore the important potential role of let-7 family in mediating the pulmonary vascular remodeling in PH rats and proliferation of primary cultured PASMCs. Furthermore, we will investigate the underlying mechanisms responsible for the down-regulation of let-7 in pulmonary arteries in hypoxia-induced PH rats(focusing on positive feedback regulation between c-myc and let-7) and the downstream signaling that let-7 inhibits vascular remodeling(focusing on let-7/RAS/c-myc/bmi-1/p16). 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 target.