基于网络药理学和实验验证探讨槲皮素治疗心力衰竭的分子机制

Study on Mechanism of Quercetin in Heart Failure Based on Network Pharmacology and Experimental Validation

目的:通过网络药理学和分子对接方法预测槲皮素治疗心力衰竭的治疗靶点及相关信号通路,通过离体细胞模型进一步明确其作用机制。方法:通过SwissTargetPrediction,TargetNet数据库获取槲皮素药理作用相关靶点;通过在线人类孟德尔遗传数据库(OMIM),GeneCards,疗效药物靶点数据库(TTD)数据库获取心力衰竭相关靶点;使用STRING数据库进行蛋白质-蛋白质相互作用(PPI)网络分析,建立槲皮素-心力衰竭靶点PPI网络图;利用Cytoscape 3.7.2软件对槲皮素抗心力衰竭网络节点进行筛选分析,使用DAVID工具平台对所得靶点进行基因本体(GO)与京都基因与基因组百科全书(KEGG)富集分析。利用离体细胞心力衰竭模型,验证药物的抗心力衰竭作用,为药物的基因预测和验证提供基础。结果:预测结果显示槲皮素与心力衰竭相关靶点23个,其中关键靶点11个,包括基质金属蛋白酶-9(MMP-9),雄激素受体(AR),凝血因子2(F2),胰岛素样生长因子1受体(IGF1R),表皮生长因子受体(EGFR),Janus激酶2(JAK2),细胞色素P450家族19A1(CYP19A1),雌激素受体-1(ESR1),肿瘤坏死因子(TNF),C型蛋白酪氨酸激酶受体(PTPRC),细胞色素P450家族17A1(CYP17A1)等。结果提示槲皮素可能具有干预心肌细胞和内皮细胞增殖、能量代谢调控等生理过程的功能,参与调节缺氧诱导因子1(HIF-1)信号通路、类固醇激素生物合成等信号通路。结论:槲皮素治疗心力衰竭具有多靶点-多途径-多通路的特点,作用机制可能与其调节MMP-9,EGFR等关键基因,参与心血管细胞增殖和能量代谢等生物过程相关。

Objective:To predict the therapeutic targets and related signaling pathways of quercetin in the treatment of heart failure(HF)by network pharmacology and molecular docking methods,and further clarify its mechanisms through in vitro cell model. Method:The pharmacological targets of quercetin were obtained by SwissTargetPrediction and Targetnet databases;the heart failure related targets were obtained by Online Mendelian Inheritance in Man(OMIM),GeneCards and Therapeutic Target Database(TTD)databases;the protein-protein interaction(PPI) network was analyzed by STRING database(Search Tool for Recurring Instances of Neighbouring Genes),and the PPI network diagram of quercetin for heart failure target was established. Cytoscape 3.7.2 software was used for analyzing and screening the anti-heart failure network nodes of quercetin,and the obtained targets were enriched with gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis by DAVID database. In order to explore the mechanism of quercetin in the treatment of heart failure,we used cell model to verify the function in heart failure treatment. Results: The predicted results showed that there were 23 targets for the treatment of heart failure,such as Matrix Metallopeptidase-9(MMP-9),androgen receptor(AR),coagulation factor 2(F2),insulin like growth factor 1 receptor(IGF1 R),epidermal growth factor receptor(EGFR),janus kinase-2(JAK2),cytochrome P450 family 19 subfamily A member 1(CYP19 A1),estrogen receptor-1(ESR1),tumor necrosis factor(TNF),protein tyrosine phosphatase receptor type C(PTPRC)and cytochrome P450 family 17 subfamily A member 1(CYP17 A1)etc.The results suggest that quercetin may play a role in the treatment of heart failure by intervening in the physiological processes of cardiovascular cell proliferation and metabolism,regulating hypoxia-inducible factor 1(HIF-1)signaling pathway and steroid hormone biosynthesis. Conclusion: Quercetin has the characteristics of multi-target,multi-channel and multi-channel in the treatment of heart failure. It may play a role in the treatment of heart failure by regulating MMP-9,EGFR and other key genes,participating in the biological process of cardiac and vascular cell proliferation and metabolism.