软骨寡聚基质蛋白通过BMPs/BMPRII通路介导肺动脉平滑肌细胞表型转化

Pulmonary arterial hypertension (PAH) is a malignant disease and the pathological mechanism is unclear. Pulmonary arterial remodeling is a major pathological change of PAH and Pulmonary artery smooth muscle (PASMCs) phenotype transformation is the start step in it. Cartilage oligomeric matrix protein (COMP) is an extracellular matrix component newly discovered. On our previous study found that pulmonary artery pressure increased obviously in COMP-/- mice and we preliminary confirmed that COMP expression decreased significantly in PAH model rats. It was suggested that there was some relationship between COMP and PAH, but the mechanism remains to be elucidated. It is reported that COMP can combine with BMP2 directly and block BMPs/BMPRII signal transmission. BMPRII dysfunction can cause PAH. But it is unknown the relationship between COMP and PAH. We speculate that COMP may participate in pulmonary artery remodeling via adjusting the expressions of different BMP subtypes and affecting the BMPs/BMPRII signal transmission. To test our hypothesis, we will explicit the effects of COMP on PASMCs phenotypic transformation and clarify the role of BMPs/BMPRII pathways in it in vitro and in vivo by the methods of molecular biology, laser confocal microscopy, immunohistochemical technique, and etc. This topic will enrich the knowledge of the extracellular matrix on PAH, and provide a new therapeutic target for PAH treatment.

肺动脉高压（PAH）是一种恶性疾病。肺动脉重塑是PAH的主要病理改变，肺动脉平滑肌（PASMCs）表型转化是肺动脉重塑的起始步骤。软骨寡聚基质蛋白(COMP)是新近被发现的细胞外基质成分。我们的前期研究发现敲除了COMP基因的小鼠，肺动脉压明显增高;并初步证实PAH模型大鼠COMP表达明显减少。提示COMP与PAH相关，但其机制尚待阐明。文献报道COMP可与BMP2直接结合，阻断BMP2/BMPRII介导的信号传递。但COMP与PAH之间的关系尚无报道。我们推测COMP可能通过调节BMP不同亚型，影响BMPs/BMPRII信号，参与肺动脉重构，导致PAH发生。为证实这一假说，我们将采用分子生物学、激光共聚焦、免疫组化等技术，从整体和细胞两个水平观察COMP对PASMCs表型转化的影响及BMPs/BMPRII通路在其中发挥的作用。本课题将丰富PAH发生的相关知识，为PAH治疗提供新的靶点

细胞外基质蛋白在肺高压发病中发挥重要作用，但是一种新近发现的细胞外基质成分——软骨寡聚基质蛋白在缺氧诱导的肺高压发病中的作用尚不清楚。本研究采用高效液谱和分子生物学手段，通过在体、离体和细胞水平的缺氧性肺高压模型，首次发现：（1）缺氧导致大鼠、小鼠及牛的肺动脉平滑肌表达软骨寡聚基质蛋白（COMP）减少；（2）COMP减少引起肺动脉平滑肌收缩表型蛋白标志物表达减少；（3）COMP减少引起NOX2和NOX4升高，SOD2下降，导致细胞内部ROS水平变化；（4）COMP与肺动脉平滑肌BMPR2表达水平有关；（5）肺动脉平滑肌BMPR2表达水平与细胞内ROS水平变化相关。上述结果证实了我们提出“COMP通过BMPR2通路引起肺动脉平滑肌细胞表型转化”的假说，为肺高压的防治提供一个新靶点。