自噬在FHL1促进香烟暴露大鼠肺动脉平滑肌细胞增殖中的作用及其机制

Cigarette smoke induced pulmonary vascular remodeling occurs earlier than COPD and hypoxic pulmonary hypertension，and the study of the mechanism is helpful for early prevention and treatment of pulmonary hypertension. Pulmonary artery smooth muscle cells (PASMCs) proliferation is an important cause of pulmonary vascular remodeling.FHL1 promotes PASMCs proliferation and causes pulmonary vascular remodeling in a variety causes of pulmonary hypertension. I have found that FHL1 also promotes PASMCs proliferation on rats exposed to cigarette smoke and then is involved in pulmonary vascular remodeling, but the mechanism is not clear. Researches have found that ①FHL1 inhibits skeletal muscle autophagy and autophagy related to PASMCs proliferation,②FHL1 is associated with AKT phosphorylation, and PI3K/AKT/mTOR signaling pathway regulates autophagy of rats PASMCs with hypoxic pulmonary hypertension. On this project, we use cigarette smoke exposure, FHL1 intervention and autophagy intervention to study the role of autophagy in FHL1 induced proliferation of rats pulmonary artery smooth muscle and PASMCs which are exposed to cigarette smoke extract and to explore its relationship with PI3K/AKT/mTOR signaling pathway. This project will help us to clarify mechanism of FHL1 induced PASMCs proliferation on cigarette smoke exposure rats, and to understand mechanism of cigarette smoke on pulmonary vascular remodeling. These results provide a theoretical basis for early prevention and treatment of pulmonary hypertension.

香烟暴露所致的肺血管重构较其所致COPD及低氧性肺动脉高压发生更早，研究其机制有利于早期防治肺动脉高压。肺动脉平滑肌细胞（PASMCs）增殖是香烟导致肺血管重构的重要原因。FHL1促进PASMCs增殖参与多种原因所致的肺动脉高压，本人前期研究发现FHL1促进香烟暴露大鼠PASMCs增殖参与肺血管重构，但其机制不明。研究已发现①FHL1抑制骨骼肌自噬，自噬与PASMCs增殖有关；②FHL1影响AKT磷酸化，而PI3K/AKT/mTOR信号通路调节低氧大鼠PASMCs中的自噬。本项目拟通过香烟、FHL1及自噬等多种干预手段，从动物及细胞水平，研究自噬在FHL1促进香烟暴露大鼠PASMCs增殖中的作用，并明确其与PI3K/AKT/mTOR信号通路的关系。本项目有助于明确FHL1促进香烟暴露大鼠PASMCs增殖的机制，有助于探讨香烟暴露大鼠肺血管重构的机制，为早期防治肺动脉高压提供理论基础。

香烟暴露所致的肺血管重构较其所致COPD及低氧性肺动脉高压发生更早，研究其机制有利于早期防治肺动脉高压。肺动脉平滑肌细胞（PASMCs）增殖是香烟导致肺血管重构的重要原因。FHL1促进PASMCs增殖参与多种原因所致的肺动脉高压，本人前期研究发现FHL1促进香烟暴露大鼠PASMCs增殖参与肺血管重构，但其机制不明。研究已发现①FHL1抑制骨骼肌自噬，自噬与PASMCs增殖有关；②FHL1影响AKT磷酸化，而PI3K/AKT/mTOR信号通路调节低氧大鼠PASMCs中的自噬。本项目拟通过香烟、FHL1及自噬等多种干预手段，从动物及细胞水平，研究自噬在FHL1促进香烟暴露大鼠PASMCs增殖中的作用，并明确其与PI3K/AKT/mTOR信号通路的关系。项目实施过程中，通过对大鼠香烟烟雾暴露、大鼠PASMCs进行CSE干预，并结合FHL1-siRNA转染、自噬抑制剂干预及AKT/mTOR干预等方法，多方位多角度对自噬在FHL1促进香烟暴露大鼠PASMCs增殖中的作用及其与TGF-β/Smad2/3、AKT/mTOR的关系进行探讨。结果发现抑制FHL1可显著降低CSE诱导的PASMCs增殖，伴TGF-β及p-Smad2/3降低。我们还发现FHL1-si RNA转染逆转CSE诱导的PASMCs增殖过程中AKT/mTOR减少和LC3增加。因此研究认为：FHL1参与CSE诱导的PASMCs增殖可能与TGF-β/Smad2/3信号和自噬途径有关。本研究结论进一步明确FHL1促进香烟暴露大鼠PASMCs增殖的机制，有助于探讨香烟暴露大鼠肺血管重构的机制，为早期防治肺动脉高压提供理论基础。