Decoding dexmedetomidine's multiple mechanisms in atherosclerosis: effects on lipid metabolism, inflammation, cholesterol efflux, and foam cell formation.

Atherosclerosis is a leading cause of cardiovascular disease and is characterized by dysregulated lipid metabolism and chronic vascular inflammation. Dexmedetomidine (DEX) has been reported to exert anti-inflammatory, antioxidant and lipid-lowering effects across several disease settings, yet its potential therapeutic impact on atherosclerosis remains unclear. In this study, we investigated the anti-atherosclerotic efficacy of DEX and explored the underlying mechanisms in vivo and in vitro. An atherosclerosis model was established by feeding ApoE−/− mice a Western diet for 13 weeks, followed by intraperitoneal injection of DEX (100 µg/kg) for 16 days. Then, RAW264.7 macrophages were exposed to oxidized LDL (Ox-LDL; 50 µg/mL) for 24 h in the presence or absence of DEX (10 µM). Anti-atherosclerotic effects were assessed using Western blotting, quantitative PCR, Oil Red O staining, pathological staining, cholesterol quantification, and serum lipid profiling. DEX treatment markedly reduced lipid-rich plaques in the aortic root and attenuated aortic atherosclerotic lesions in ApoE−/− mice, while also significantly lowering serum glucose (Glu), Ox-LDL, LDL-cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG). In addition, DEX promoted fecal cholesterol excretion, decreased cholesterol accumulation in the liver and intestine, and suppressed systemic expression of TNF-α, IL-6, and IL-1β. Consistently, in Ox-LDL–stimulated RAW264.7 cells, DEX limited foam cell formation and enhanced cholesterol efflux. Mechanistically, both in vivo and in vitro findings indicated that DEX upregulated SIRT1 and ABCA1 expression, whereas pharmacologic inhibition of SIRT1 with selisistat abolished these protective effects, supporting a central role for the SIRT1/ABCA1 axis. Collectively, these results suggest that DEX mitigates atherosclerosis by activating the SIRT1/ABCA1 pathway, thereby alleviating inflammation, foam cell formation, lipid metabolic dysfunction, and impaired cholesterol export, and they highlight DEX as a promising candidate for the treatment and prevention of atherosclerotic disease.