Rab6 GTPase参与内质网应激调控肺血管重构的机制研究

Pulmonary hypertension is a malignant pulmonary vascular disease. Pulmonary artery smooth muscle cells (PASMCs) phenotypic modulation is an important initial event during pulmonary vascular remodeling and pulmonary hypertension formation. It is very important for the prevention and treatment of pulmonary hypertension to clarify the molecular mechanism of PASMCs phenotypic modulation. Previous studies have demonstrated that the activation of unfolded protein response (UPR) is associated with the development of pulmonary vascular remodeling and pulmonary hypertension. And our previous study demonstrated that Rab6 can regulate PASMCs phenotypic modulation under hypoxia. Based on these, we observe the effect of over-expression or silence Rab6 on UPR, the expression change of cell phenotype markers when rat PASMCs exposed to hypoxia, and analyze changes of signal pathway and smooth muscle cell proliferation, apoptosis, autophagy. To explore how Rab6 regulates PASMCs phenotypic modulation by mediating the UPR under hypoxia, and then affects the progress of pulmonary vascular remodeling. We will initially clarify the mechanisms of Rab6 mediated UPR and its regulatory mechanism to PASMCs phenotypic modulation under hypoxia, to provide new views for the prevention and treatment of pulmonary hypertension.

肺动脉高压（PAH）是一种恶性进展性疾病。肺动脉平滑肌细胞（PASMC）的表型转化是肺血管重构、PAH形成中的关键起始步骤。研究发现内质网应激（ERS）、未折叠蛋白反应（UPR）的激活参与肺血管重构及PAH的发生发展，且我们前期研究发现Rab6可以调节低氧诱导的PASMC表型转化，因此，Rab6可能通过对UPR的调控影响PASMC的表型转化，进而影响PAH的发生发展。本项目以大鼠PASMC为研究对象，观察低氧状况下过表达或沉默Rab6对平滑肌细胞UPR的影响、细胞表型标志分子的变化，相关信号通路及细胞增殖、凋亡等功能状态的变化，确定Rab6通过UPR调控PASMC表型转化的作用机制。在动物模型上，研究Rab6是否参与了PAH的发生发展。通过此研究以期初步阐明低氧状况下Rab6介导UPR的机制及其对PASMC表型转化的调控机制，从而为肺血管重构、肺动脉高压的防治提供新的思路。

肺血管重构是肺动脉高压的基本病理特征，其中肺动脉平滑肌细胞（PASMC）的表型转化是肺血管重构、肺动脉高压形成中的关键起始步骤。内质网应激、未折叠蛋白反应（UPR）的激活参与肺血管重构及肺动脉高压的发生发展，且我们前期研究发现Rab6可以调节低氧诱导的PASMC表型转化，因此，Rab6可能通过对UPR的调控影响PASMC的表型转化，进而影响PAH的发生发展。本研究中我们发现1、低氧能促进RPASMCs表型转化和内质网应激，且内质网应激比表型转化更早发生。2、Rab6参与了低氧诱导的RPASMCs 表型转化和内质网应激过程。3、敲低ATF6基因可下调低氧诱导的内质网应激相关蛋白的表达，并抑制低氧诱导的PASMCs表型转化。因此Rab6可通过对UPR的调控影响PASMC的表型转化，进而影响肺动脉高压的发生发展，从而为肺动脉高压的防治提供关键靶点。