南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (8): 1198-1206.doi: 10.12122/j.issn.1673-4254.2021.08.11

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槲皮素治疗心力衰竭的分子机制:基于网络药理学与分子对接方法

谭 鑫，鲜 维，陈永锋，李小荣，王其一，康品方，王洪巨   

  1. 蚌埠医学院第一附属医院心血管内科，心脑血管病研究中心，生理学教研室，安徽 蚌埠 233000
  • 出版日期:2021-08-20 发布日期:2021-09-07

Exploring the therapeutic mechanism of quercetin for heart failure based on network pharmacology and molecular docking

TAN Xin, XIAN Wei, CHEN Yongfeng, LI Xiaorong, WANG Qiyi, KANG Pinfang, WANG Hongju   

  1. Department of Cardiology, First Affiliated Hospital of Bengbu Medical College, Research Center of Cardio Cerebrovascular Diseases, Department of Physiology, Bengbu Medical College, Bengbu 233000, China
  • Online:2021-08-20 Published:2021-09-07

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摘要： 目的 基于网络药理学和分子对接研究槲皮素治疗心力衰竭(HF)的分子机制。方法 利用TCMSP、PharmMapper、CTD和GeneCards数据库得到槲皮素和HF相关靶点，通过在线Venn网站得到槲皮素-HF交集靶点，构建蛋白质相互作用网络后导入Cytoscape3.7.2得到槲皮素治疗HF的核心靶点。通过R包进行GO、KEGG通路富集分析，利用Auto Dock Vina进行分子对接。通过蛋白质免疫印迹检测槲皮素处理HF细胞模型的AKT1、Phospho-AKT（Ser473）、eNOS、MMP9和Caspase-3的蛋白水平。结果 分析得到80个槲皮素-HF交集靶点，槲皮素治疗HF核心靶点5个：AKT1、CASP3、MAPK1、MMP9和MAPK8。GO分析中，生物过程集中在对肽类激素的反应、磷脂酰肌醇介导的信号传导、脂多糖的反应、对细菌来源分子的反应和炎症反应的调节等。KEGG通路富集分析表明富集最显著的信号通路为：脂质与动脉粥样硬化通路、癌症中的蛋白多糖、PI3K-AKT信号通路、糖尿病心肌病和MAPK信号通路。分子对接显示槲皮素对5个核心靶点具有良好的结合活性。蛋白质免疫印迹结果显示，100 μmol/L 槲皮素可明显降低心力衰竭细胞AKT1、Phospho-AKT（Ser473）、eNOS、MMP9和Caspase-3水平（P<0.01）。结论 槲皮素可能通过调节AKT1-eNOS-MMP9通路抗凋亡从而改善心力衰竭的病理变化。

关键词: 槲皮素；心力衰竭；分子对接；网络药理学

Abstract: Objective To investigate the molecular mechanism of quercetin in the treatment of heart failure (HF) based on network pharmacology and molecular docking. Methods Quercetin and HF-related targets were obtained using TCMSP, PharmMapper, CTD and GeneCards databases, and quercetin-HF intersection targets were obtained through the online website Venn; the protein interaction network was constructed and imported into Cytoscape 3.7.2 to identify the core targets of quercetin in the treatment of HF. GO and KEGG pathway enrichment analyses were performed using R package, and molecular docking was performed using Auto Dock Vina. The protein levels of AKT1, phospho-AKT (Ser473), eNOS, MMP9, and caspase-3 in quercetin-treated HF cell models were detected using protein immunoblotting. Results We identified 80 quercetin-HF intersectional targets (AKT1, CASP3, MAPK1, MMP9, and MAPK8) and 5 core targets of quercetin for treatment of HF. GO analysis suggested that the therapeutic effect of quercetin for HF was mediated mainly by such biological processes as responses to peptide hormones, phosphatidylinositol-mediated signalling, responses to lipopolysaccharides, responses to molecules of bacterial origin and regulation of inflammatory responses. KEGG pathway enrichment analysis identified lipid and atherosclerosis pathway, proteoglycans in cancer, PI3K-AKT signaling pathway, diabetic cardiomyopathy and MAPK signaling pathway as the most significantly enriched signaling pathways. Molecular docking showed a good binding activity of quercetin to the 5 core targets. The results of protein immunoblotting showed that 100 μmol/L quercetin significantly reduced AKT1, phospho-AKT (Ser473), eNOS, MMP9 and caspase-3 levels in the cell models of HF (P<0.01). Conclusion Quercetin improves the pathological changes in HF possibly by regulating the AKT1-eNOS-MMP9 pathway to inhibit cell apoptosis.

Key words: quercetin; heart failure; molecular docking; network pharmacology