Intraperitoneal Isoastragaloside II Attenuated Western Diet-Induced Atherosclerosis in Male ApoE-/- Mice with Lipid-Lowering and Anti-Inflammatory Effects

Background: Atherosclerosis is driven by lipid accumulation, vascular inflammation, and macrophage foam cell formation. Nutritional therapy, employing natural products with bioactive compounds, is a potential avenue for treating atherosclerosis. Isoastragaloside II (Iso-AS-II) is a bioactive saponin isolated from the medicinal and edible plant Astragalus membranaceus (Huangqi), but its role in atherosclerosis has not been investigated. Methods: In this study, we investigated the effects of Iso-AS-II (i.p., 5 mg/kg) in male ApoE-/- mice fed a Western diet (WD) and identified potential mechanisms through network pharmacology and transcriptomic analyses. In parallel, oxidized low-density lipoprotein (ox-LDL)-induced RAW 264.7 foam cells were used to evaluate the efficacy of Iso-AS-II in reducing foam cell accumulation and inflammation. Results: Iso-AS-II reduced aortic lesion area, plaque macrophage infiltration, and smooth muscle cell content, and lowered serum lipids (TC, TG and LDL-C) and inflammatory cytokines (TNF-α, IL-6, MCP-1, M-CSF and IL-12). Network pharmacology and transcriptomics suggested modulation of lipid metabolism and inflammatory pathways. In macrophages, Iso-AS-II suppressed foam cell formation, accompanied by downregulation of Cd36 and Msr1 and upregulation of Abca1 and Abcg1, and exerted anti-inflammatory effects by reducing IL-1β, IL-6, and TNF-α levels. Conclusions: This exploratory study provides the first evidence that Iso-AS-II reduces atherosclerotic burden in WD-fed ApoE-/- mice, and suggests that these effects involve improved systemic lipid homeostasis, suppression of inflammation, and inhibition of macrophage foam-cell formation, supporting its potential as a natural anti-atherosclerotic agent.