抑癌基因Axin2低表达在缺氧肺动脉高压血管重构中的作用及其分子机制

Pulmonary hypertension is a highly malignant disease, known as cardiovascular disease cancer, but its pathogenesis is unclear and its incidence is rising rapidly. The mechanisms of pulmonary hypertension are key scientific issues for researchers working to solve. We early detected the abnormal expression of a tumor suppressor gene-Axin2 in lung tissues from patients with pulmonary hypertension; we also found that Axin2 knockout increased intima-to-media ratio of PAs. We hypothesized that: Axin2 may be associated with hypoxic pulmonary hypertension. We intend to use patient samples, knockout animals and vitro experiments to verify the hypothesis above from the four aspects: 1. Define the regulatory role of Axin2 for pulmonary hypertension. 2. Determine the effects of hypoxia on Axin2 expression during hypoxic pulmonary hypertension. 3. Determine the effects of Axin2 in hypoxic pulmonary vasoconstriction and vascular remodeling. 4. Determine the mechanisms involved in Axin2 knockout induced pulmonary vasoconstriction and vascular remodeling. This research will reveal the molecular mechanism of hypoxic pulmonary hypertension, furthermore provide a new theoretical basis for the diagnosis and treatment of pulmonary hypertension.

肺动脉高压是一种极度恶性疾病，被称为心血管病中的癌症，病因未明，其发病率目前正迅速攀升。揭示肺动脉高压病因是科学界致力于解决的关键科学问题。前期我们在肺动脉高压病人肺组织中检测出一种抑癌基因-Axin2的表达异常，且Axin2基因敲除小鼠肺血管壁明显增厚。由此我们推测：Axin2可能与缺氧肺动脉高压的发生密切相关。本项目拟通过基因敲除鼠及体外实验等从以下四个方面验证该科学假说：1、明确Axin2对于肺动脉高压的调控作用。2、确定缺氧通过影响Axin2的表达调控肺动脉高压。3、研究Axin2参与缺氧肺血管收缩和血管重构的过程。4、鉴定Axin2参与缺氧肺血管收缩和重构的机制。本课题的实施将有助于揭示缺氧肺动脉高压的分子机制，为肺动脉高压的诊断和治疗提供新的理论依据。

本课题通过研究抑癌基因Axin2在肺动脉高压发病机制中的作用探讨了肺动脉高压发病的分子机制。主要结果：（1）Axin2在肺动脉高压病人肺血管中表达明显下调，且调控肺动脉平滑肌细胞的增殖、凋亡和迁移能力，表明Axin2是肺动脉高压发生发展的一个新的负性调控因子。（2）Axin2在肺动脉高压发生中的调控机制主要通过影响β-catenin的表达；（3）缺氧通过孤儿核受体Nur77调控Axin2-β-catenin信号通路。这些结果提示，Axin2是调控缺氧性肺动脉高压形成的重要靶分子，缺氧通过Nur77抑制Axin2表达，上调β-catenin，促进肺动脉平滑肌细胞增殖与凋亡抑制，从而促进肺动脉高压血管重构。