The Compatibility of Astragali Radix and Angelicae Sinensis Radix Attenuates Atherosclerosis by Suppressing Vascular Endothelial PANoptosis via the p38 MAPK/p53 Pathway: A Multi-Omics and Experimental Study.

Previous studies have reported that the combination of Astragali Radix and Angelicae Sinensis Radix (AR-ASR) can ameliorate atherosclerosis (AS) through anti-inflammatory effects; however, the exact mechanistic underpinnings still await further clarification. The present study investigates the anti-atherosclerotic action of AR-ASR from the perspective of PANoptosis (encompassing apoptosis, pyroptosis, and necroptosis). To ascertain the chief active ingredients of the AR plus ASR mixture, UPLC-MS/MS detection was utilized. To predict potential therapeutic targets, a multi-faceted bioinformatics strategy was applied, integrating transcriptomics, single-cell sequencing, network pharmacology, molecular docking, and molecular dynamics simulations. In vivo, male ApoE-deficient mice were allocated at random into the model cohort, AR-ASR low-, medium-, and high-dose groups (AR-ASR L, AR-ASR M, and AR-ASR H, respectively), atorvastatin group (ATV), and control group (age-matched wild-type C57BL/6J mice). Atherosclerosis was induced by 12 weeks of high-fat diet feeding, followed by 4 weeks of oral gavage treatment. Assessment parameters included aortic intimal hyperplasia thickness, serum lipid levels, vascular inflammatory factor expression, endothelial function, and the gene and protein expression levels of PANoptosis- and p38MAPK/p53 signaling pathway-related molecules. For in vitro experiments, POVPC-stimulated AVECs were used as an oxidative damage model and then treated with AR-ASR-containing serum. Cell proliferation activity, cell injury rate, and the expression levels of PANoptosis markers and p38MAPK/p53 signaling pathway-related molecules were measured. Furthermore, in the presence of a p38MAPK agonist, the protective effect of AR-ASR on AVECs and its underlying mechanism were investigated. Bioinformatics analysis suggested that AR-ASR modulates PANoptosis and interferes with AS via the p38MAPK/p53 signaling axis. In vivo, AR-ASR treatment reduced serum lipid levels, attenuated aortic intimal hyperplasia, decreased plasma inflammatory cytokine levels and vascular inflammatory factor expression, improved endothelial function, and suppressed both vascular PANoptosis and p38MAPK/p53 pathway activation. In vitro, POVPC induced oxidative damage and PANoptosis in AVECs. AR-ASR-containing serum promoted AVEC viability, reduced LDH release, inhibited the expression of PANoptosis-related markers, and downregulated p38MAPK/p53 signaling pathway protein expression. Furthermore, in the presence of a p38MAPK agonist, the inhibitory effects of AR-ASR on cellular PANoptosis and p38MAPK/p53 pathway activation were significantly attenuated. The AR-ASR compatibility suppresses p38MAPK/p53 pathway activation, thereby inhibiting vascular endothelial PANoptosis-driven inflammatory responses and ameliorating atherosclerotic vascular pathology.