HIMF调节内皮-间质转化、平滑肌细胞增殖对低氧性肺血管重塑的作用及机制研究

Pulmonary artery smooth muscle cells (PASMCs) proliferation is major cell mechanism of hypoxic pulmonary hypertension.However, more and more people pay attention to endothelial-mesenchymal transition of hypoxic pulmonary hypertention.Recent studies have shown that hypoxia-induced mitogenic factor (HIMF) is characteristic of hypoxic induction and mitogen and specific lung. It may play a pivotal role in the hypoxic pulmonary vascular remodeling. In this project, we seek to examine three important aspects of the HIMF-dependent mechanism: First, whether hypoxia upregulates the expression of HIMF expression in the pulmonary artery endothelium and smooth muscle cells, leading to PASMC proliferation, endothelial-mesenchymal transition, and vascular remodeling; second, whether HIMF mediates Ca2+ mobilization via PLC-IP3 pathway to regulate transformation growth factorβ1 (TGF-β1), Cyclin E/D1, CDK 2/4 via PKC/MAPKs and PI3K/Akt/mTOR signal pathway, leading to PASMC proliferation and endothelial-mesenchymal transition. Finally, we will determine whether interference of PLC-IP3, PKC/MAPKs, PI3K/Akt/mTOR, and TGF-β1 signal pathway alleviates pulmonary vascular remodeling in animal models. We will test our hypothesis using primary cultured PASMCs and endothelial cell, chronic hypoxia animal models and COPD patient with pulmonary hypertension. The results generated from this project may provide new information on the cellular and molecular mechanism of hypoxic pulmonary hypertension, and identify therapeutic targets for the development of novel treatment for the dreadful disease.

肺动脉平滑肌细胞增殖是低氧性肺动脉高压（HPH）主要细胞机制，内皮-间质转化机制最近倍受关注。新发现低氧诱导丝裂原因子（HIMF）是低氧诱导促分裂原作用的生长因子，具有 "肺组织特异性"，可能在HPH发病中起关键作用。本项目将探讨低氧是否上调肺动脉内皮细胞、平滑肌细胞HIMF表达，通过PLC-IP3通路，增加细胞内钙离子浓度,Ca2+作为第二信使激活PKC/MAPKs和PI3K/Akt/mTOR通路上调TGF-β1和细胞周期蛋白Cyclin E/D1、CDK 2/4促进肺动脉内皮-间质转化和平滑肌细胞增殖，导致肺血管重塑形成。本研究将从低氧原代培养的肺动脉内皮细胞、平滑肌细胞，低氧性肺动脉高压动物模型和COPD肺动脉高压患者三个层面验证我们的假设，并探讨其细胞分子机制，揭示HPH的发病机制，为HPH的防治提供新的靶点，也为新药的研究奠定理论基础。