Melatonin prevents endothelial cell pyroptosis via regulation of long noncoding RNA MEG3/miR‐223/NLRP3 axis

作者：Yong Zhang, Xin Liu, Xue Bai, Lin Yuan, Zhange Li, Jiangbo Fu, Mingqi Li, Tong Zhao, Huan Yang, Ranchen Xu, Jiamin Li, Jin Hyun Ju, Benzhi Cai, Chaoqian Xu, Baofeng Yang · 发表于：Journal of Pineal Research · 年份：2017 · DOI：10.1111/jpi.12449 · 被引用次数：404 · 研究领域：Inflammasome and immune disorders、IL-33, ST2, and ILC Pathways、Atherosclerosis and Cardiovascular Diseases

Abstract Atherosclerosis ( AS ) is an inflammatory disease linked to endothelial dysfunction. Melatonin is reported to possess substantial anti‐inflammatory properties, which has proven to be effective in AS . Emerging literature suggests that pyroptosis plays a critical role during AS progression. However, whether pyroptosis contributes to endothelial dysfunction and the underlying molecular mechanisms remained unexploited. This study was designed to investigate the antipyroptotic effects of melatonin in atherosclerotic endothelium and to elucidate the potential mechanisms. In this study, high‐fat diet ( HFD )‐treated ApoE −/− mice were used as an atherosclerotic animal model. We found intragastric administration of melatonin for 12 weeks markedly reduced the atherosclerotic plaque in aorta. Meanwhile, melatonin also attenuated the expression of pyroptosis‐related genes, including NLRP 3, ASC , cleaved caspase1, NF ‐κB/ GSDMD , GSDMD N‐termini, IL ‐1β, and IL ‐18 in aortic endothelium of melatonin‐treated animals. Consistent antipyroptotic effects were also observed in ox‐ LDL ‐treated human aortic endothelial cells ( HAEC s). We found that lnc RNA MEG 3 enhanced pyroptosis in HAEC s. Moreover, MEG 3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR‐223 and to increase NLRP 3 expression and enhance endothelial cell pyroptosis. Furthermore, knockdown of miR‐223 blocked the antipyroptotic actions of melatonin in ox‐ LDL ‐treated HAEC s. ...