期刊
CELL COMMUNICATION AND SIGNALING
卷 17, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12964-019-0406-7
关键词
Atherosclerosis; NLRP3 inflammasome; NFAT5; Hypertonic stress; Endothelium
类别
资金
- National Program on Key Basic Research Project (973 Program) of China [2014CB541600]
- National Natural Science Foundation of China [11372364, 11532004, 11832008]
- Fundamental Research Funds for the Central Universities [2019CDYGYYB002, CDJZR235517]
- Foundation for University Key Young Teacher of Chongqing
- Drug Development Center, China Medical University from The Featured Areas Research Center Program within the Ministry of Education (MOE) in Taiwan
- China Postdoctoral Science Foundation [2016 M590866]
Background How high-salt intake leads to the occurrence of many cardiovascular diseases such as atherosclerosis is a fundamental question in pathology. Here we postulated that high-salt-induced NFAT5 controls the inflammasome activation by directly regulating NLRP3, which mediates the expression of inflammatory- and adhesion-related genes in vascular endothelium, resulting in the formation of atherosclerosis. Methods Atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice which accumulate cholesterol ester-enriched particles in the blood due to poor lipoprotein clearance capacity were used as the atherosclerosis model in vivo. Cultured endothelial cells (ECs) and monocytes under high-salt condition were used to explore the atheroprone role of the activation of NFAT5-NLRP3 inflammasome in vascular endothelium in vitro. Bioinformatic analysis and chromatin immunoprecipitation assay were used to identify the DNA binding sites of NFAT5 on promoters of NLRP3 and IL-1 beta. Results We first observe that high-salt intake promotes atherosclerosis formation in the aortas of ApoE(-/-) mice, through inducing the expression of NFAT5, NLRP3, and IL-1 beta in endothelium. Overexpression of NFAT5 activates NLRP3-inflammasome and increases the secretion of IL-1 beta in ECs partly via ROS. Chromatin immunoprecipitation assay demonstrates that NFAT5 directly binds to the promoter regions of NLRP3 and IL-1 beta in endothelial cells subjected to the high-salt environment. Conclusions Our study identifies NFAT5 as a new and essential transcription factor that is required for the early activation of NLRP3-inflammasome-mediated endothelium innate immunity, contributing to the formation of atherosclerosis under hypertonic stress induction.
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