Melatonin ameliorates atherosclerosis by suppressing S100a9-mediated vascular inflammation

作者全名："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"

作者地址："[Chen, Liyuan; Pan, Lina; Zhang, Xutao; Hu, Houyuan] Third Mil Med Univ, Southwest Hosp, Dept Cardiol, Chongqing 400038, Peoples R China; [Zhou, Zhou] Chongqing Univ, Ctr Neurointelligence, Sch Med, Chongqing 400030, Peoples R China; [Wang, Xue; Deng, Ping; Yang, Lingling; Yu, Zhengping; Pi, Huifeng] Third Mil Med Univ, Dept Occupat Hlth, Key Lab Electromagnet Radiat Protect, Minist Educ, Chongqing 400038, Peoples R China; [Reiter, Russel J.] UT Hlth San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA; [Liu, Chang] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurol, Chongqing 400010, Peoples R China; [Cheng, Juan] Chongqing Med Univ, Affiliated Hosp 1, Dept Obstet, Chongqing 400042, Peoples R China"

通信作者："Hu, HY (通讯作者)，Third Mil Med Univ, Southwest Hosp, Dept Cardiol, Chongqing 400038, Peoples R China.; Zhou, Z (通讯作者)，Chongqing Univ, Ctr Neurointelligence, Sch Med, Chongqing 400030, Peoples R China.; Pi, HF (通讯作者)，Third Mil Med Univ, Dept Occupat Hlth, Key Lab Electromagnet Radiat Protect, Minist Educ, Chongqing 400038, Peoples R China."

来源：EUROPEAN JOURNAL OF PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001074450500001

JCR分区：Q1

影响因子：4.2

年份：2023

卷号：957

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Atherosclerosis; Vascular inflammation; Melatonin; S100a9

摘要："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-& kappa;B 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-& kappa;B 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."

基金机构："National Natural Science Foundation of China [82070467, 82001264, 81770433]; Youth Top- notch Talent Support Program of Chongqing City [CQYC201905014]; National Postdoctoral Program for Innovative Talents [BX201700107]"

基金资助正文："<BOLD> Financial support </BOLD> This work was supported by the National Natural Science Foundation of China (No. 82070467, 82001264 and 81770433) , the Youth Top- notch Talent Support Program of Chongqing City (CQYC201905014) and the National Postdoctoral Program for Innovative Talents (BX201700107) ."