Sclerostin在体-肺分流性肺血管病理性重构中的作用机制

肺动脉平滑肌细胞（PASMCs）表型转换导致的肺血管病理性重构是先天性心脏病相关肺动脉高压（CHD/PAH）特征性的病理改变，但其具体机制尚不清楚且至今无针对肺血管病理性重构的靶向药物。本课题组前期筛选并验证发现CHD/PAH肺组织及重构的肺血管中骨硬化蛋白(SOST) 的表达显著下降；免疫共沉淀发现SOST可与Wnt/β-catenin通路膜受体LRP5/6结合；SOST可诱导PASMCs增殖和凋亡表型转换；SOST基因敲除大鼠显示轻度PAH表型。据此我们推测：SOST通过Wnt/β-catenin通路诱导PASMCs的表型转换，进而促进CHD/PAH肺血管病理性重构的发生。本研究拟在人肺组织、动物模型、PASMCs、SOST敲除及过表达大鼠等水平，阐明SOST在CHD/PAH肺血管病理性重构中的作用及潜在机制，以期为CHD/PAH肺血管病理性重构的靶向药的研发提供理论依据。

Pulmonary arterial smooth muscle cells (PASMCs) phenotype transformation induced pulmonary vascular pathological remodeling is the characteristic pathological change of congenital heart disease-associated pulmonary hypertension (CHD/PAH), but the specific mechanism is not clear and there are still no targeted drugs aimed at pulmonary vascular pathological remodeling. Our team's preliminary screening and verification found that the level of sclerostin (SOST) significantly decreased in lung tissues and remodeled pulmonary vessels of CHD/PAH; Co-immunoprecipitation found that SOST can bind to the membrane receptor LRP5/6 of Wnt/β-catenin pathway; SOST can induce the proliferation of PASMCs and apoptotic phenotype transformation; SOST knockout rats show a mild PAH phenotype. Based on these findings, we speculate that SOST induces phenotypic transformation of PASMCs through the Wnt/β-catenin pathway, and further promotes the genesis of pulmonary vascular pathological remodeling of CHD/PAH. This study，utilizing human lung tissues, animal models, PASMCs, SOST knockout and over-expressing rats, intends to elucidate the roles and potential mechanisms of SOST in the pulmonary vascular pathological remodeling of CHD/PAH and provides theoretical evidences for the development of targeted drugs for the pulmonary vascular pathological remodeling of CHD/PAH.