REDD1调控肺动脉平滑肌细胞线粒体稳态的机制及其在低氧肺动脉重构中的作用

Hypoxia induces the imbalance of pulmonary artery smooth muscle cells (PASMCs) mitochondria homeostasis lead to pulmonary arterial remodeling, which is the important pathological alteration of pulmonary hypertension (PH). Regulated in development and DNA damage responses 1 (REDD1) is an important transcript factor. Recent study demonstrated that REDD1 promoted the release and activity of osteosarcoma cells mitochondrial ROS, co-participated in skeletal muscle cells mitochondria biosynthesis with PGC-1α, activated autophagy in tumor cells by inhibition of mTOR and activated the mitophagy in nerve cells, all of which regulating mitochondria homeostasis. However, it is unclear whether REDD1 regulates the PASMCs mitochondria homeostasis by the similar mechanism in pulmonary arterial remodeling induced by hypoxia. The current research is to investigate the mechanism of REDD1 in regulating PASMCs mitochondria homeostasis and its role in hypoxic pulmonary arterial remodeling. This study will focus on the mechanisms and functions of REDD1-PGC-1α, REDD1-mTOR, and REDD1/Parkin signaling pathways in the process of hypoxia-induced imbalance of PASMCs mitochondria homeostasis. This research will provide scientific experimental data for further clarifying the pathogenesis of hypoxic pulmonary hypertension and finding new therapeutic target point.

低氧诱导肺动脉平滑肌细胞（PASMCs）线粒体稳态的失衡参与肺动脉重构，是低氧肺动脉高压（PH）的重要致病因素。发育及DNA损伤反应调节基因1（REDD1）是一种重要的转录因子。近期研究发现，REDD1促进骨肉瘤细胞线粒体活性氧（ROS）释放及活性；与PGC-1α参与促进骨骼肌细胞线粒体的生物合成；抑制mTOR激发肿瘤细胞自噬以及激活神经细胞线粒体自噬等共同参与线粒体稳态的调控。但是，REDD1是否通过调节PASMCs线粒体功能、线粒体生物合成以及自噬清除等机制调控线粒体稳态参与低氧肺动脉重构，目前尚不清楚。本项目拟探讨低氧条件下，REDD1调控PASMCs线粒体稳态的机制及其在低氧肺动脉重构中的作用，重点研究REDD1-PGC-1α、REDD1-mTOR、REDD1/Parkin信号通路在低氧PASMCs线粒体稳态的调控作用，为进一步阐明PH的发病机制及新的可能治疗靶点提供科学依据。

课题研究按照原定计划进行，研究计划中主要内容包括：观察低氧条件下人肺动脉平滑肌细胞（HPASMCs）中REDD1水平的变化；设计针对人REDD1基因的RNA干扰序列及过表达序列，探究REDD1对人肺动脉平滑肌细胞（HPASMCs）线粒体功能、生物合成、自噬清除和增殖、凋亡的调控作用及其分子机制；使用REDD1基因敲除大鼠建立低氧PH大鼠模型，观察其对大鼠缺氧性肺血管重构的影响及对肺小动脉线粒体稳态以及自噬的影响。我们研究发现：低氧肺动脉高压患者肺动脉平滑肌细胞中REDD1较正常对照组明显升高，同时在低氧肺动脉高压大鼠模型中显著升高。敲除REDD1后，可以明显逆转低氧肺动脉高压以及肺血管重构。此外，我们发现敲除REDD1后可以缓解低氧PASMCs异常增殖、凋亡耐受以及迁移；同时，REDD1敲除后低氧PASMC中线粒体功能障碍明显缓解，而这种缓解是通过调控自噬所致。除原定研究内容之外，我们还探讨了REDD1也参与了肺腺癌的进展。