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 NLRP3, 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 (HAECs). We found that lncRNA MEG3 enhanced pyroptosis in HAECs. Moreover, MEG3 acted as an endogenous sponge by sequence complementarity to suppress the function of miR‐223 and to increase NLRP3 expression and enhance endothelial cell pyroptosis. Furthermore, knockdown of miR‐223 blocked the antipyroptotic actions of melatonin in ox‐LDL‐treated HAECs. Together, our results suggest that melatonin prevents endothelial cell pyroptosis via MEG3/miR‐223/NLRP3 axis in atherosclerosis, and therefore, melatonin replacement might be considered a new strategy for protecting endothelium against pyroptosis, thereby for the treatment of atherosclerosis associated with pyroptosis.

中文翻译：

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褪黑素通过调节长的非编码RNA MEG3 / miR-223 / NLRP3轴来防止内皮细胞的热解

动脉粥样硬化（AS）是一种与内皮功能障碍有关的炎性疾病。据报道，褪黑激素具有重要的抗炎特性，已被证明对AS有效。新兴文献表明，细胞凋亡在AS进展中起着至关重要的作用。然而，焦磷酸化是否会导致内皮功能障碍，其潜在的分子机制尚待开发。这项研究旨在研究褪黑激素在动脉粥样硬化内皮中的退热作用，并阐明其潜在机制。在这项研究中，高脂饮食（HFD）治疗的ApoE ^-/-小鼠用作动脉粥样硬化动物模型。我们发现褪黑激素在胃内给药12周可显着减少主动脉粥样硬化斑块。同时，褪黑素还减弱了褪黑素治疗动物的主动脉内皮中与凋亡相关基因的表达，包括NLRP3，ASC，裂解的caspase1，NF-κB/ GSDMD，GSMDD N-末端，IL-1β和IL-18。在经ox-LDL处理的人主动脉内皮细胞（HAEC）中也观察到了一致的镇咳作用。我们发现lncRNA MEG3增强了HAEC中的细胞凋亡。此外，MEG3通过序列互补性起到内源性海绵的作用，以抑制miR-223的功能并增加NLRP3表达并增强内皮细胞的凋亡。此外，敲除miR-223可以阻断褪黑素在经ox-LDL处理的HAEC中的解热作用。一起，