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J Pineal Res. 2018 Mar;64(2). doi: 10.1111/jpi.12449. Epub 2017 Dec 20.

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

Author information

1
Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
2
Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin, China.
3
Faculty of Medicine, Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia.

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 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.

KEYWORDS:

MEG3; atherosclerosis; endothelial cell pyroptosis; melatonin; miR-223

PMID:
29024030
DOI:
10.1111/jpi.12449
[Indexed for MEDLINE]

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