Mechanism of compound danshen dripping pills in ameliorating atherosclerosis in ApoE-/-mice with hyperlipidemia

ZHANG Shuang-li; GE Shi-hui; GE Zi-meng; ZHANG Bei-bei; MIAO Ming-san; WANG Jun; MIAO Jin-xin

doi:10.20251/j.cnki.1003-3734.2025.23.013

Abstract：Objective:To conduct a network pharmacology-based investigation of the potential targets and mechanisms of compound danshen dripping pills(CDDP)in ameliorating atherosclerosis(AS),with experimental validation in ApoE-/-mice.Methods:The active components and therapeutic targets of CDDP were screened,and AS-related targets were predicted to identify common targets.A"disease-drug-component-target"network and a PPI network were constructed,followed by GO and KEGG pathway enrichment analyses.An AS model was established in 36 ApoE-/-mice by feeding a high-fat diet,while12 C57BL/6 mice served as a blank control group and 12 ApoE-/-mice fed a normal diet served as a model control group.After 12 weeks,body weight and plasma levels of TC,TG,and LDL-C were measured to confirm the successful establishment of the AS model.The ApoE-/-mice were then randomly divided into a positive control group receiving atorvastatin calcium tablets(2.6 mg·kg-1·d-1)and CDDP high-,medium-,and low-dose groups(210,105 and 52.5 mg·kg-1·d-1),with continuous modeling and drug administration for another 12 weeks.The effects of CDDP on body weight;plasma levels of TC,TG,LDL-C,and HDL-C;serum IL-6,TNF-α,IL-4,and IL-13;hepatic levels of TG,NEFA and FC;and pathological changes in the aorta and liver(assessed via hematoxylin and eosin staining)were evaluated.Additionally,WB analysis was performed to assess the expression of macrophage-related inflammatory pathway proteins,including PPARγ,NF-κB,and p-NF-κB.Results:A total of 76 active components and 197 targets of CDDP were identified,along with 2 552 AS/hyperlipidemia(HLP)-related targets.A total of 123 overlapping targets between CDDP and AS/HLP were obtained.The key active compounds in CDDP for AS/HLP treatment were identified as tanshinone IIA,luteolin,and quercetin,which primarily exerted their effects through the PPAR,NF-κB,MAPK,and TNF signaling pathways.In vivo experiments demonstrated that CDDP significantly increased body weight in the ApoE-/-HFD group(P<0.01),reduced plasma TC,TG,and LDL-C levels,and increased HDL-C levels(P<0.05).Additionally,CDDP significantly decreased serum IL-6 and TNF-α levels while increasing IL-4 and IL-13 levels(P<0.01).Hepatic TG,NEFA,and FC levels were significantly reduced(P<0.01,P<0.05).Histopathological analysis revealed that CDDP alleviated endothelial injury and plaque deposition in the aorta and mitigated hepatic lipid accumulation.Moreover,CDDP significantly upregulated PPARγ expression and downregulated NF-κB and p-NF-κB protein levels(P<0.01,P<0.05).Conclusion:CDDP exerts anti-atherosclerotic effects by modulating macrophage-associated inflammatory responses,potentially through the PPARγ/NF-κB signaling pathway.