Quercetin,the key constituent of Astragali Radix,modulates ferroptosis in PASMCs and attenuates hypoxia pulmonary hypertension via the MAPK signaling pathway  

黄芪主成分槲皮素通过MAPK通路调控PASMCs铁死亡抗低氧性肺动脉高压的研究

作　　者：Xia Li Beibei Cheng Junlan Tan Jiajing Wan Yuhong Wang Aiguo Dai 李霞;程贝贝;谭骏岚;万佳婧;王宇红;戴爱国(湖南省中医药研究院,湖南长沙410208;湖南中医药大学医学院呼吸疾病研究室,湖南长沙410208;血管生物学与转化医学湖南省重点实验室/湖南省高校重点实验室,湖南长沙410208;湖南中医药大学科技创新中心,湖南长沙410208)

机构地区：[1]Hunan Academy of Chinese Medicine,Changsha 410208,Hunan,China [2]Department of Respiratory Diseases,Medical School,Hunan University of Chinese Medicine,Changsha 410208,Hunan,China [3]Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine,Changsha 410208,Hunan,China [4]Science and Technology Innovation Center,Hunan University of Chinese Medicine,Changsha 410208,Hunan,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2024年第8期714-729,共16页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No.82305214);Hunan Province’s Natural Science Fund(Grant No.2023JJ40401);Hunan Administration of Traditional Chinese Medicine(Grant No.B2023024);Hunan Provincial Department of Education Outstanding Youth Project(Grant No.22B0394);State Key Laboratory Project of Chinese Medicine Powder and Innovative Drugs Project(Grant No.21PTKF1002).

摘　　要：This study delved into the mechanism by which the principal component of Astragali Radix regulated ferroptosis in the context of hypoxia-induced pulmonary hypertension,employing a combination of network pharmacology and experimental validation techniques.Active constituents of Astragali Radix and their corresponding targets were identified using the TCMSP database,while therapeutic targets associated with hypoxia-induced pulmonary hypertension were sourced from the GeneCards database.The Venn online tool facilitated the identification of overlapping targets between the active constituents of Astragali Radix and hypoxia-induced pulmonary hypertension.Interaction network diagrams depicting the relationship between Astragali Radix’s active constituents and their targets were constructed using Cytoscape software,with core targets and sub-networks identified using the CytoHubba plug-in.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were conducted using the DAVID database.Additionally,the FerrDb database was consulted to analyze genes implicated in regulating ferroptosis.The investigation revealed 18 active constituents selected from Astragali Radix,with quercetin emerging as the key component.A total of 35 potential targets associated with Astragali Radix in regulating ferroptosis and addressing hypoxia-induced pulmonary hypertension were predicted.Experimental validation demonstrated that quercetin could inhibit the MAPK signaling pathway,resulting in reduced Fe2+and lipid peroxide levels,increased GPX4 expression,and the reversal of ferroptosis.In summary,this study elucidated the fundamental constituents and pivotal signaling pathways through which Astragali Radix modulated ferroptosis and mitigated hypoxia-induced pulmonary hypertension.Specifically,quercetin,a core constituent of Astragali Radix,was observed to inhibit ferroptosis in pulmonary arterial smooth muscle cells via the MAPK pathway and alleviate hypoxia-induced pulmonary hypertension.本文基于网络药理学和实验验证探讨黄芪主成分调控铁死亡抗低氧性肺动脉高压的作用机制。利用TCMSP数据库获取黄芪活性成分及其所对应的靶标;通过GeneCards数据库获取低氧性肺动脉的治疗靶标;利用Venn在线工具获得黄芪活性成分和低氧性肺动脉高压的共同作用靶点。运用Cytoscape软件构建黄芪活性成分、靶标间相互作用网络关系图,并使用CytoHubba插件获得核心靶点以及核心子网络。应用DAVID数据库进行基因本体(GO)富集分析和京都基因与基因组百科全书(KEGG)通路富集分析。检索FerrDb数据库,获得调控铁死亡的基因并进行分析,最后探析黄芪活性成分、低氧性肺动脉高压、铁死亡三者关系并作出预测,并结合实验验证。结果显示,从黄芪中筛选出18种有效活性成分,其中槲皮素是其关键成分,预测得到35个黄芪调控铁死亡抗低氧性肺动脉高压的可能作用靶标。进一步通过实验验证发现,槲皮素可抑制MAPK信号通路激活,进而抑制Fe2+、脂质过氧化物水平,升高GPX4表达,逆转铁死亡。该研究初步利用网络药理学挖掘出了黄芪调控铁死亡抗低氧性肺动脉高压的核心成分及关键信号通路;并揭示了槲皮素作为黄芪的核心成分能够通过MAPK通路抑制PASMCs铁死亡,逆转低氧性肺动脉高压。

关 键 词：Network pharmacology Astragali Radix QUERCETIN PASMCs Ferroptosis Hypoxia pulmonary hypertension 

分 类 号：R944[医药卫生—药剂学]