基于色氨酸代谢探讨麻黄根原花青素防治低氧性肺动脉高压作用机制

Hypoxic pulmonary arterial hypertension (HPAH), which is an important pathological process of triggering pulmonary heart diseases, may lead to right heart failure and death, therefore, the prevention and treatment of HPAH is urgent. Based on our previous findings and to elucidate the mechanism of the preventative and therapeutic effects of proanthocyanidins in the roots of Ephedra sinica Staf (Mahuanggen) on hypoxia pulmonary arterial hypertension, this project will use HPAH rat models. Firstly, date processing methods of the untargeted metabolomics will be used to rapidly discover the metabolism of proanthocyanidins during HPAH. Secondly, we will focus on tryptophan metabolic pathway, which plays a key role in the development of HPAH and a tryptophan-targeted analysis method will be established for four types of biological samples (lung, right ventricle, small intestine and serum). Relationship among metabolic constituents of proanthocyanidins, preventative and therapeutic effects on HPAH and tryptophan-related metabolic biomarkers will be discovered through quantitative correlation analysis to reveal the preventative and therapeutic effects of proanthocyanidins in Mahuanggen on HPAH from the perspective of tryptophan metabolism and verify the feasibility of targeting tryptophan pathway for early diagnosis, prevention and treatment of HPAH. This project will give insights into the discovery and mechanistic investigation of tryptophan pathway-targeted anti-HPAH TCMs.

低氧性肺动脉高压(HPAH)是引发肺源性心脏病的关键病理环节，可发展为右心衰竭导致死亡，目前尚无有效治疗方法，因此HPAH的早期防治迫在眉睫。本项目在前期研究发现基础上，为深入揭示麻黄根原花青素防治HPAH的作用机制，采用HPAH大鼠模型为主要研究载体，首先利用非目标性代谢组学数据处理方法，快速发现麻黄根原花青素组分在防治HPAH发展过程中的体内代谢变化规律；然后以与HPAH发生、发展密切相关的色氨酸代谢通路为切入点，建立大鼠肺、右心室、小肠和血清四个部位的色氨酸代谢通路靶向分析方法，通过对原花青素组分“入血成分谱-防治HPAH药理活性-干预色氨酸代谢标志物”三者间的量化关联分析，从色氨酸代谢调控角度探讨麻黄根原花青素防治HPAH的分子机制，并验证该通路用于HPAH早期诊断及药物防治网络靶标的可行性。本项目将为以色氨酸代谢通路为靶点的HPAH防治中药的开发及作用机制研究提供新的思路和方法。

低氧性肺动脉高压(HPAH)是一类严重威胁人类健康的进展性和致命性疾病，近年来发病率逐年增加，但尚无有效治疗方法。本项目首次发现麻黄根富含原花青素二聚体类成分（PERE），并具有HPAH防治作用。首先利用柱色谱和超高效液相色谱-高分辨质谱联用技术发现PERE主要集中于麻黄根乙酸乙酯部位，并进一步优化了PERE富集方法，低损耗分离出麻黄宁H和I等成分。基于大鼠肺动脉平滑肌细胞和RAW264.7细胞的实验结果表明，PERE具有良好的体外抗氧化和抗炎活性。进一步采用连续低氧法建立大鼠HPAH模型，发现PERE能够明显减轻低氧引起的右心室收缩压升高、右心室肥厚、肺组织小动脉管壁增厚和平滑肌细胞增生，色氨酸代谢通路的靶向分析和肠道菌群研究结果表明，PERE可以回调HPAH引起的血清中色氨酸、犬尿喹啉酸和黄尿酸水平升高及肠道菌群改变。本项目扩大了麻黄根的临床应用范围和原花青素类成分提取的植物来源，不仅为麻黄根的深入开发和利用提供了有益参考，也为药典中麻黄根质量标准的完善提供了科学依据。