Exploring the mechanisms of Kanli Granule in the treatment of chronic heart failure based on network pharmacology combined with experimental verification

Abstract Background and Objectives: Kanli granule (KG) is a Traditional Chinese Medicine (TCM), which has a significant effect on chronic heart failure (CHF). KG takes "warming and invigorating the heart and kidney Yang Qi, promoting water and blood circulation" as the treatment principle, which can make the heart Yang vibrate, the kidney water transpiration, and the blood promote the circulation of water without the danger of stopping warter blood stasis. However, due to the complexity of TCM, the action mechanism of KG is unclear. In this study, we employed a network pharmacology approach combined with experimental verification to investigate the mechanism of KG in the treatment of CHF. Materials and methods: The active ingredients and targets of KG were searched by TCMSP and TCM database@Taiwan databases, and the CHF-related targets were collected from DisGeNET, OMIM and TTD databases. Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome (KEGG) signal pathway analysis were carried out through DAVID database. Furthermore, the bubble diagrams of GO analysis and KEGG signal pathway analysis are made on OmicShare platform. The network diagram of "herbs–ingredients–targets–pathways" was constructed by Cytoscape3.7.0 software. We established a TAC induced CHF mice model to verify the protective mechanism of KG. Results: 30 active ingredients of KG were screened for the prevention and treatment of CHF, and 37 targets for the prevention and treatment of CHF by the active components of KG, including SERCA2a, PLB. GO analysis showed that there were 219 items related to biological process, 32 items related to cellular composition and 42 items related to molecular function. There are 81 related KEGG signaling pathways, including calcium signaling pathway. The results of animal experiments showed that KG significantly improved cardiac function in CHF mice by reducing LVEF, FS, NT -proBNP, and KG significantly improved cardiac structure in CHF mice by decreasing LVIDd, LVPWd, and the extent of cardiac fibrosis. Further mechanistic studies revealed that KG upregulated SERCA2a expression and activity to ameliorate CHF. Conclusion: KG may prevent and treat CHF by acting on calcium signaling pathway, increasing SERCA2a expression and improving cardiac function and cardiac structure.