Cedrol mitigates atherosclerosis by inhibiting foam cell formation and inflammatory response via suppression of NOD-like receptor family pyrin domain containing 3 inflammasome

BACKGROUND: Foam cell formation and inflammation are critical to atherosclerosis development. Cedrol is a well-known natural sesquiterpene with a wide range of pharmacological properties. In this study, we aimed to elucidate the influence of cedrol on foam cell formation and inflammatory reaction during atherosclerosis. METHODS: ApoE-/- mice were fed a high-fat diet and treated with cedrol (60 and 120 mg/kg). Aortic lesions were determined by Oil Red O staining. Inflammation in the aorta was evaluated by ELISA and reverse transcription quantitative polymerase chain reaction. Immunohistochemical staining showed NOD-like receptor family pyrin domain containing 3 (NLRP3) and cleaved caspase-1 expression in aortic roots. RAW264.7 mouse macrophages were stimulated with oxidized low-density lipoprotein (ox-LDL; 80 μg/ml) and treated with cedrol (1, 5, and 10 μM). Cholesterol accumulation and foam cell formation were evaluated. Western blotting assessed the levels of macrophage cholesterol efflux and NLRP3 signaling-related proteins. Nuclear factor kappa B (NF-κB) signaling and reactive oxygen species (ROS) production were examined to explore upstream mechanisms. RESULTS: Cedrol improved serum lipid profiles and alleviated the pathological features of atherosclerosis in mice. Cedrol inhibited the expression of inflammatory cytokines and inactivated the NLRP3 inflammasome in atherosclerosis mice. In RAW264.7 cells, cedrol significantly suppressed ox-LDL-induced cholesterol accumulation and foam cell formation. Cedrol also inhibited ox-LDL-induced inflammation and NLRP3 inflammasome activation, while the NLRP3 activator nigericin reversed these effects. Mechanistically, cedrol suppressed NF-κB activation and reduced total and mitochondrial ROS production in vitro. CONCLUSION: Cedrol alleviated atherosclerosis development by suppressing inflammation and foam cell formation via inactivation of the NLRP3 inflammasome, which was mediated through inhibition of NF-κB signaling and oxidative stress.