摘要
目的通过动物实验探究左西孟旦(levosimendan,LEVO)对低氧肺动脉高压(hypoxic pulmonary hypertension,HPH)的作用,使用网络药理学方法与分子对接技术进一步探索其潜在作用机制。方法构建HPH大鼠模型,检测右心收缩压及右心重构指数;通过HE、Masson和VG染色分析大鼠肺组织病理学变化。检索Swiss Target Prediction、DrugBank Online、BatMan、Targetnet、SEA、PharmMapper数据库,筛选药物靶点;从GeneCards、OMIM数据库中检索疾病靶点;确定二者交集靶点后,构建“药物-靶点-疾病”网络;构建蛋白互作网络并筛选出核心靶点;使用DAVID数据库进行GO和KEGG通路富集分析;用AutoDock软件对核心靶点进行分子对接。结果动物实验结果表明,LEVO对HPH具有明显治疗作用;网络药理学结果显示,SRC、HSP90AA1、MAPK1、PIK3R1、AKT1、HRAS、MAPK14、LCK、EGFR、ESR1等是发挥治疗作用的关键靶点;分子对接显示,LEVO与度值前5的核心靶点均对接良好。结论LEVO可能通过多靶点发挥对HPH的治疗作用。
Aim To explore the efficacy of levosimendan on hypoxia pulmonary hypertension through animal experiments,and to further explore the potential mechanism of action using network pharmacological methods and molecular docking technique.Methods The rat model of hypoxia pulmonary hypertension was constructed to detect right heart systolic pressure and right heart remodeling index.HE,Masson,and VG staining were used to analyze the changes of rat lung histopathology.Search the Swiss Target Prediction,DrugBank Online,BatMan,Targetnet,SEA,and PharmMapper databases were used to screen for drug targets.Disease targets were retrieved from the GeneCards,OMIM databases.The“drug-target-disease”network was constructed after identification of the two intersection targets.The protein interaction network was constructed and the core targets were screened out.GO and KEGG pathway enrichment analysis were performed using the DAVID database.Molecular docking of the core targets was performed with the AutoDock software.Results The results of animal experiments showed that levosimendan had obvious therapeutic effect on hypoxia pulmonary hypertension.The network pharmacology results showed that SRC,HSP90AA1,MAPK1,PIK3R1,AKT1,HRAS,MAPK14,LCK,EGFR and ESR1 were the key targets to play a therapeutic role.Molecular docking showed good docking of levosimendan with all the top five core targets with degree values.Conclusions Levosimendan may exert a therapeutic effect on hypoxia-induced pulmonary hypertension through multiple targets.
作者
张晓丹
谢玉良
高梦丹
袁奥雪
李涵飞
祝田田
ZHANG Xiao-dan;XIE Yu-liang;GAO Meng-dan;YUAN Ao-xue;LI Han-fei;ZHU Tian-tian(School of Pharmacy,Xinxiang Medical University,Xinxiang Henan 453003,China;Henan International Joint Laboratory of Cardiovascular Reconstruction and Drug Intervention,Xinxiang Henan 453003,China;Xinxiang Key Laboratory of Cardiovascular Reconstruction Intervention and Molecular Targeted Therapy,Xinxiang Henan 453003,China)
出处
《中国药理学通报》
CAS
CSCD
北大核心
2024年第3期565-573,共9页
Chinese Pharmacological Bulletin
基金
国家自然科学基金资助项目(No81800051)
河南省科技发展计划项目(No212102310319)。
关键词
左西孟旦
低氧肺动脉高压
动物实验
网络药理学
分子对接
作用机制
levosimendan
hypoxic pulmonary hypertension
animal experiments
network pharmacology
molecular docking
mechanism of action
