LOX-1在低氧诱导肺动脉高压内皮细胞间质转化中的作用及机制研究

Pulmonary arterial hypertension（PAH）is characterized by vessels stenosis caused by pulmonary vascular remodeling,which may be closely related to endothelial-mesenchymal transition(EndMT). Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a multifunctional receptor, plays critical roles in multiple signal transduction pathways and is involved in the genesis and development of multiple cardiovascular diseases. However, the role of LOX-1 in EndMT-mediated pulmonary vascular remodeling in PAH remains unknown.Our pilot study showed that the expression of LOX-1 mRNA and protein was up-regulated in pulmonary arteries in hypoxia-induced PAH rats and pulmonary artery endothelial cells, and LOX-1 and the biomarkers of EndMT（α-SMA and vimentin） were co-expressed and increased in the pulmonary arterial intima in PAH rats induced by hypoxia. We will be planning to explore the important/potential role of LOX-1 in mediating EndMT in PAH rats and human pulmonary artery endothelial cells. Furthermore, we will investigate the underlying mechanisms responsible for the up-regulation of LOX-1 in the pulmonary arterial intima in hypoxia-induced PAH rats (focusing on HIF-1α/miR-21/PDCD4/AP-1/LOX-1and HIF-1α/ miR-21/LRRFIP1/NF-κB/LOX-1 pathways) and the downstream signaling that LOX-1 promotes EndMT (focusing on LOX-1/TGF-β1-R- Smad/Snail pathway). This study will contribute to the understanding of the pathogenesis of PAH, and provide new strategies to seek for the new drugs directing at LOX-1 target.

植物凝集素样氧化性低密度脂蛋白受体-1（LOX-1）在多种心血管疾病的发生与发展中起重要作用。然而，LOX-1 是否参与肺动脉高压（PAH） 肺血管重构时内皮细胞间质转化（EndMT）尚不清楚。预实验发现，低氧诱导PAH 时大鼠肺动脉和内皮细胞中LOX-1表达增高；LOX-1与EndMT标志蛋白（α-SMA和Vimentin）在低氧诱导PAH大鼠肺小动脉内膜中均显著上调。本项目拟通过在体动物与细胞实验，查明LOX-1 在PAH 时EndMT发生过程中的重要作用，探讨LOX-1上调的机制（HIF-1α/miR-21/PDCD4/AP-1/LOX-1和HIF-1α/ miR-21/LRRFIP1/NF-κB/LOX-1通路）以及LOX-1促EndMT的机制（LOX-1/TGF-β1-R/Smad/Snail通路）。本项目将有助于阐明PAH 的发病机制，为寻找防治PAH 的新靶点奠定基础。

植物凝集素样氧化性低密度脂蛋白受体-1（LOX-1）在多种心血管疾病的发生与发展中起重要作用。然而，LOX-1 是否参与肺动脉高压（PAH） 肺血管重构时内皮细胞间质转化（EndMT）尚不清楚。预实验发现，低氧诱导PAH 时大鼠肺动脉和内皮细胞中LOX-1表达增高；LOX-1与EndMT标志蛋白（α-SMA和Vimentin）在低氧诱导PAH大鼠肺小动脉内膜中均显著上调。本项目拟通过在体动物与细胞实验，查明LOX-1 在PAH 时EndMT发生过程中的重要作用，探讨LOX-1上调的机制以及LOX-1促EndMT的机制。结果发现：（1）低氧PH过程中发生了显著地 EndMT；LOX-1介导了低氧 PH 中的 EndMT；（2）LOX-1通过调控 TGF-β1/p-Smads/Snail 信号通路介导低氧 PH 时EndMT；（3）低氧通过HIF-1α/miR-21/PDCD4/c-Jun和HIF-1α/miR-21/LRRFIP1/NF-κB通路上调LOX-1的表达介导PH时EndMT。本项目主要研究了LOX-1在低氧诱导肺动脉高压内皮细胞间质转化中的作用及机制，将有助于阐明PAH的发病机制，为寻找防治PAH的新靶点奠定基础。