Melatonin ameliorates atherosclerosis by suppressing S100a9-mediated vascular inflammation

• Published in: European journal of pharmacology 2023-10, Vol.957, p.175965-175965, Article 175965
• Main Authors: Chen, Liyuan, Wang, Xue, Liu, Chang, Deng, Ping, Pan, Lina, Yang, Lingling, Cheng, Juan, Zhang, Xutao, Reiter, Russel J., Yu, Zhengping, Pi, Huifeng, Zhou, Zhou, Hu, Houyuan
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Melatonin; S100a9; Vascular inflammation
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175965

Atherosclerosis (AS)-associated cardiovascular diseases are predominant causes of morbidity and mortality worldwide. Melatonin, a circadian hormone with anti-inflammatory activity, may be a novel therapeutic intervention for AS. However, the exact mechanism is unclear. This research intended to investigate the mechanism of melatonin in treating AS. Melatonin (20 mg/kg/d) was intraperitoneally administered in a high-fat diet (HFD)-induced AS model using apolipoprotein E-deficient (ApoE−/−) mice for 12 weeks. Immunohistochemical and immunofluorescence analyses, data-independent acquisition (DIA)-based protein profiling, ingenuity pathway analysis (IPA), and western blotting were employed to investigate the therapeutic effects of melatonin in treating HFD-induced AS. An adeno-associated virus (AAV) vector was further used to confirm the antiatherosclerotic mechanism of melatonin. Melatonin treatment markedly attenuated atherosclerotic lesions, induced stable phenotypic sclerotic plaques, inhibited macrophage infiltration, and suppressed the production of proinflammatory cytokines in ApoE−/− mice with HFD-induced AS. Notably, DIA-based quantitative proteomics together with IPA identified S100a9 as a pivotal mediator in the protective effects of melatonin. Moreover, melatonin significantly suppressed HFD-induced S100a9 expression at both the mRNA and protein levels. The overexpression of S100a9 significantly activated the NF-κB signaling pathway and markedly abolished the antagonistic effect of melatonin on HFD-induced vascular inflammation during atherogenesis. Melatonin exerts a significant antiatherogenic effect by inhibiting S100a9/NF-κB signaling pathway-mediated vascular inflammation. Our findings reveal a novel antiatherosclerotic mechanism of melatonin and underlie its potential clinical use in modulating AS with good availability and affordability. [Display omitted] •Melatonin effectively reduced the severity of high-fat diet-induced atherosclerosis in ApoE−/− mice.•Melatonin suppressed the high-fat diet-induced vascular inflammatory response during atherogenesis.•Melatonin ameliorated atherosclerosis by suppressing S100a9/NF-κB axis-mediated vascular inflammation.•S100A9 was highly enriched in infiltrated macrophages in human atherosclerotic lesions.