Effect and Mechanism of Shenlian Formula in Treatment of Atherosclerotic Cardiovascular Disease Based on Network Pharmacology / 中国实验方剂学杂志

ABSTRACT

Objective:To analyze active components， its targets and signaling pathways of Shenlian formula based on network pharmacology， and explore the molecular mechanism of Shenlian formula in the treatment of atherosclerotic cardiovascular disease （ASCVD）， in order to provide a basis for the rational interpretation of the prescription compatibility of Shenlian formula. Method:Major chemical compounds of the formula were obtained by SymMap and Systematic pharmacology database and analysis platform of Traditional Chinese Medicine （TCMSP）， its target proteins were obtained by SymMap and ETCM Databases， and the pathogenic genes responsible for of ASCVD were obtained by DisGeNET and GEO Datebases. Protein targets of drugs and pathogenic genes of diseases were overlapped to obtain predicted targets of Shenlian Formula for ASCVD. Proteins-proteins interactions （PPI） network was built through the String Datebase. The Cytoscape 3.6.0 was used to explore the key compounds and targets of Shenlian formula on ASCVD. Then gene ontology （GO） enrichment and Kyoto Encyclopedia of Genes and Genomes （KEGG） signaling pathway were analyzed to screen out the key targets of Shenlian Formula. Rat I/R model was adopted as representative disease model of ASCVD for experimental verification. Result:There were 59 candidate compounds， 67 predicted targets and 29 key targets of Shenlian formula on ASCVD. Key targets mainly included cyclooxygenase 2 （PTGS2）， estrogen receptor 1 （ESR1） and TP53. GO analysis showed that the biological functions of potential genes of Shenlian formula in treatment of ASCVD were mainly related to apoptotic， nitric oxide biosynthetic process， response to estradiol， angiogenesis， inflammatory response and oxidative stress and acute-phase response. KEGG pathway enrichment results showed that the pathways of potential genes of Shenlian formula in treatment of ASCVD mainly involved TNF signaling pathway， phosphatidylinositol-3 kinase （PI3K）/ protein kinase B （Akt） signaling pathway， hypoxia induction factor-1 （HIF-1） signaling pathway and apoptosis. Among them， the regulatory effect of Shenlian formula on apoptosis may act on not only TP53， but also different signaling pathways of apoptosis respectively， thus playing a synergistic effect. <italic>In vivo</italic> experimentation confirmed that Shenlian formula could significantly reduce the myocardial infarction area， improve the myocardial histopathological changes， and especially reduce myocardial mitochondrial injury. Further analysis showed that Shenlian formula can significantly inhibit the expressions of activated proteins in mitochondrial apoptosis pathway. Conclusion:Anti-atherosclerosis traditional Chinese medicine Shenlian formula could effectively intervene ASCVD， and its effect on mitochondrial apoptosis of myocardial cells is one of its mechanisms in protecting myocardial ischemia-reperfusion injury.