Melatonin ameliorates vascular endothelial dysfunction,inflammation, and atherosclerosis by suppressing the TLR4/NF‐κB system in high‐fat‐fed rabbits

Vascular endothelial dysfunction (VED) and inflammation contribute to the initiation and progression of atherosclerosis. Melatonin (MLT) normalizes lipid profile, improves endothelial function, and possesses anti‐inflammatory properties. However, the precise mechanisms are still unclear. This study investigated whether MLT could ameliorate VED, inflammation, and atherosclerosis by suppressing the Toll‐like receptor 4 (TLR4)/nuclear factor kappa B (NF‐κB) system in high‐fat‐fed rabbits. Rabbits were randomly divided into three groups that received a standard diet (control group), high‐cholesterol diet (atherosclerosis group), or high‐cholesterol diet plus 10 mg/kg/day MLT (MLT group) for 12 wk. After treatment, high‐fat diet significantly increased serum lipid and inflammatory markers in rabbits in atherosclerosis group compared with that in control group. In addition, high‐fat diet also induced VED and typical atherosclerotic plaque formation and increased intima/media thickness ratio, which were significantly improved by MLT therapy as demonstrated in MLT group. Histological and immunoblot analysis further showed that high‐fat diet enhanced the expressions of TLR4, myeloid differentiation primary response protein (MyD88), and NF‐κB p65, but decreased inhibitor of NF‐κB (IκB) expression. By contrast, MLT therapy decreased the expressions of TLR4, MyD88, and NF‐κB p65 and increased IκB expression. This study has demonstrated that MLT ameliorates lipid metabolism, VED, and inflammation and inhibits the progression of atherosclerosis in high‐fat‐fed rabbits. Moreover, our study indicates for the first time that suppression of the TLR4/NF‐κB system in local vasculature with atherosclerotic damage is important for the protective effects of MLT.