小春花总黄酮靶向肺血管重构治疗低氧性肺动脉高压的作用机制研究

Pulmonary vascular remodeling is the key structural alteration in hypoxia-induced pulmonary hypertension (HPH). Most clinical drugs treat HPH by reducing pulmonary vascular resistance instead of reversing pulmonary vascular remodeling. Therefore, it is of far-reaching significance to find new drugs targeting pulmonary vascular remodeling from Chinese medicine resources. The applicant's previous study demonstrated that total flavones of Sceptridium ternatum (FST) could treat HPH by regulating proliferation and apoptosis resistance of pulmonary artery smooth muscle cells and reversing pulmonary vascular remodeling; The mechanism may be implicated in inhibition of hypoxia-activated key factor YAP and up-regulation of BMPR1A/Smad5 signaling; In addition, protein binding and interaction may exist between YAP and BMPR1A/Smad5. Based on the results above, our group intends to clarify that FST could treat HPH by reversing pulmonary vascular remodeling and then explore the molecular biological process of FST regulating YAP-BMPR1A/Smad5 signal axis. This research will be helpful to clarify the pharmacological action and molecular mechanism of FST in the treatment of HPH, provide new discoveries for treatment of respiratory diseases from Chinese medicine and offer new strategies for exploring traditional Chinese medicine resources targeting pulmonary vascular remodeling.

肺血管重构是低氧性肺动脉高压（HPH）形成的病理生理基础，目前临床治疗药物多以降低肺血管阻力为主，难以从根本上改善肺血管重构，因此从我国丰富的中药资源中寻找靶向肺血管重构的新型药物具有深远意义。申请人前期研究发现中药植物小春花的总黄酮（FST）能够显著改善肺动脉平滑肌细胞增殖与凋亡失衡，逆转肺血管重构进而治疗HPH；其作用机制可能与抑制低氧激活的关键因子YAP及上调BMPR1A/Smad5信号相关；YAP与BMPR1A/Smad5之间可能存在蛋白结合与互作。基于此，我们拟从细胞和整体水平，首先明确FST通过靶向肺血管重构治疗HPH的药理学作用，进而探索FST调控YAP-BMPR1A/Smad5信号轴逆转肺血管重构的分子生物过程。通过本课题的研究，有助于阐明中药小春花治疗HPH的药理作用及分子机制，为中药治疗呼吸系统疾病提供新发现，也为靶向肺血管重构的中医药资源开发提供新策略。

肺血管重构是低氧性肺动脉高压（HPH）形成的病理生理基础，也是多种药物治疗不理想的根源，但目前尚未发现有效靶向肺血管重构的药物，通过细胞及动物模型筛选及药效作用鉴定发现，中药小春花符合肺动脉高压的主要治则，显著改善肺血管重构。本项目首先建立了小春花总黄酮（FST）的提取工艺，并采用大孔吸附树脂、聚酰胺树脂进行纯化，提取的总黄酮满足制剂开发的需求，通过液质联用技术对总黄酮的化学成分进行分析，并进一步建立FST的质量标准；药效学研究发现，FST可抑制低氧诱导的肺动脉平滑肌细胞增殖，促进凋亡的发生，降低HPH大鼠鼠肺微血管壁厚度，改善肺血管重构进而治疗HPH；FST显著抑制低氧下肺动脉平滑肌细胞及肺组织微血管壁YAP入核激活，伴随上下游转录因子 SOX2、TGFA、CDK6等表达同步变化，YAP磷酸化水平增加；BMPR1A/Smad5和JAK2/STAT3是YAP作用的的下游信号通路。本课题的研究，有助于阐明FST靶向肺血管重构治疗HPH的药理作用和分子机制，为中药治疗呼吸系统疾病提供新发现。