title: Melatonin ameliorates vascular endothelial dysfunction, inflammation, and atherosclerosis by suppressing the TLR4/NF-κB system in high-fat-fed rabbits.
abstract: 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.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital, Anhui Medical University, Hefei, China.
authors.forename: Ze-Ping
authors.initials: ZP
authors.lastname: Hu
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Fang
authors.forename: Nan
authors.initials: N
authors.lastname: Fang
authors.forename: Xiao-Bian
authors.initials: XB
authors.lastname: Wang
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qian
authors.forename: Zhong
authors.initials: Z
authors.lastname: Cao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Bang-Ning
authors.initials: BN
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism*; D011817:Rabbits; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D008550:Melatonin
keywords: TLR4/NF-κB system; atherosclerosis; inflammation; melatonin; vascular endothelial function