基于网络药理学探讨人参皂苷Rg1联合水蛭素治疗急性心肌梗死心肌纤维化作用机制及实验验证  

Mechanism and experimental verification of ginsenoside Rg1 combined with hirudin in treatment of myocardial fibrosis in acute myocardial infarction based on network pharmacology

作　　者：刘依 尹玉洁 韩宁馨 贾振华[1,2,3,4] LIU Yi;YIN Yu-jie;HAN Ning-xin;JIA Zhen-hua(Graduate School,Hebei Medical University,Shijiazhuang 050017,China;National Key Laboratory for Innovation and Transformation of Luobing Theory,Shijiazhuang 050035,China;Key Research Laboratory of National Administration of Traditional Chinese Medicine(Cardio-Cerebral Vessel Collateral Disease),Shijiazhuang 050035,China;Hebei Institute of Integrative Traditional Chinese and Western Medicine,Shijiazhuang 050035,China)

机构地区：[1]河北医科大学研究生学院,河北石家庄050017 [2]络病理论创新转化全国重点实验室,河北石家庄050035 [3]国家中医药管理局重点研究室(心脑血管络病),河北石家庄050035 [4]河北省中西医结合医药研究院,河北石家庄050035

出　　处：《中国药理学通报》2025年第4期753-761,共9页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金重点项目(No.2023YFC3504303)。

摘　　要：目的基于网络药理学方法预测人参皂苷Rg1(ginsenoside Rg1,G-Rg1)配伍水蛭素(hirudin)治疗急性心肌梗死(acute myocardial infarction,AMI)心肌纤维化作用机制,并通过体内、体外实验进行验证。方法利用SwissTargetPrediction、TargetNet、ETCM和ChEMBL数据库收集G-Rg1、Hirudin相应靶点,利用GeneCards、OMIM和DisGeNET数据库收集AMI与心肌纤维化相关靶点。将药物与疾病交集靶点进行蛋白互作(protein-protein interaction network,PPI)网络分析、基因本体(gene ontology,GO)功能富集分析和京都基因与基因组百科全书(kyoto encyclopedia of genomes,KEGG)通路富集分析。用结扎小鼠左冠状动脉前降支诱导的AMI小鼠模型与缺氧致人心脏微血管内皮细胞(human cardiac microvascular endothelial cells,HCMECs)损伤模型对关键靶点和通路进行验证。结果G-Rg1配伍Hirudin共229个药物靶点,AMI与心肌纤维化疾病靶点816个,二者65个交集靶点。PPI分析显示肿瘤坏死因子(tumor necrosis factor,TNF)、白细胞介素1β(interleukin-1β,IL-1β)、转化生长因子β1(transforming growth factorβ,TGFβ1)、核因子κB(nuclear factor kappa-B,NF-κB)、白细胞介素6(interleukin-6,IL-6)可能是G-Rg1配伍Hirudin治疗AMI后心肌纤维化的核心靶点;KEGG共富集了141条通路,涉及内分泌与代谢、炎症、免疫等方面,主要有TNF信号通路、PI3K/Akt信号通路及TGF-β信号通路等。体内实验证实,G-Rg1配伍Hirudin减轻小鼠AMI后心肌纤维化,下调心肌组织TNF-α、IL-1β、NF-κB、TGF-β1及smad2/3蛋白表达。体外实验证实,G-Rg1配伍Hirudin抑制细胞NF-κB/TGF-β通路,减少缺氧诱导的细胞TNF-α、IL-1β表达,叠加NF-κB抑制剂明显减少IL-1β表达,减轻细胞炎症反应。结论G-Rg1配伍Hirudin通过调控TNF-α、IL-1β等靶点及NF-κB/TGF-β通路治疗AMI后心肌纤维化,体现其多途径、多靶点的作用特点,为G-Rg1配伍Hirudin治疗AMI后心肌纤维化提供药理学依据。Aim To predict the mechanism of action of ginsenoside Rg1(G-Rg1)paired with hirudin in the treatment of myocardial fibrosis in acute myocardial infarction(AMI)based on the network pharmacology approach,and to validate it by in vivo and in vitro experiments.Methods The corresponding targets of G-Rg1 and Hirudin were collected using SwissTargetPrediction,TargetNet,ETCM and ChEMBL databases,and the targets related to AMI and myocardial fibrosis were collected using GeneCards,OMIM and DisGeNET databases.The drug-disease intersection targets were subjected to protein-protein interaction network(PPI)network analysis,gene ontology(GO)functional enrichment analysis and kyoto encyclopedia of genomes(KEGG)pathway enrichment analysis.Key targets and pathways were validated using an AMI mouse model induced by ligation of the anterior descending branch of the left coronary artery in mice versus a hypoxia-induced injury model of human cardiac microvascular endothelial cells(HCMECs).Results G-Rg1 paired with hirudin had 229 drug targets,816 AMI and myocardial fibrosis disease targets,and 65 intersecting targets.PPI analysis showed that tumor necrosis factor(TNF),interleukin-1β(IL-1β),transforming growth factor beta-1(TGF-β1),nuclear factor kappa-B(NF-κB),and interleukin-6(IL-6)might be the core targets of G-Rg1 paired with Hirudin in the treatment of post-MI myocardial fibrosis;KEGG was enriched for a total of 141 pathways involving endocrine and metabolism,inflammation,and immunity,mainly TNF signaling pathway,PI3K/Akt signaling pathway and TGF-βsignaling pathway.In vivo experiments confirmed that G-Rg1 paired with hirudin attenuated myocardial fibrosis after AMI in mice,and down-regulated the expression of TNF-α,IL-1β,NF-κB,TGF-β1,and Smad2/3 proteins in myocardial tissues.In vitro experiments confirmed that G-Rg1 paired with Hirudin inhibited cellular NF-κB/TGF-β1 pathway,reduced hypoxia-induced cellular TNF-αand IL-1βexpression,and superimposed NF-κB inhibitor significantly reduced IL-1βexpression and attenua

关 键 词：人参皂苷RG1 水蛭素 急性心肌梗死 心肌纤维化 炎症 网络药理学 

分 类 号：R-332[医药卫生] R284.1R319R364.5R542.22R542.23