Cargando…
NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium
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...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701070/ https://www.ncbi.nlm.nih.gov/pubmed/31429763 http://dx.doi.org/10.1186/s12964-019-0406-7 |
_version_ | 1783444990525964288 |
---|---|
author | Ma, Pingping Zha, Shenfang Shen, Xinkun Zhao, Yulan Li, Li Yang, Li Lei, Mingxing Liu, Wanqian |
author_facet | Ma, Pingping Zha, Shenfang Shen, Xinkun Zhao, Yulan Li, Li Yang, Li Lei, Mingxing Liu, Wanqian |
author_sort | Ma, Pingping |
collection | PubMed |
description | 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-1β. 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-1β in endothelium. Overexpression of NFAT5 activates NLRP3-inflammasome and increases the secretion of IL-1β in ECs partly via ROS. Chromatin immunoprecipitation assay demonstrates that NFAT5 directly binds to the promoter regions of NLRP3 and IL-1β 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12964-019-0406-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6701070 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-67010702019-08-26 NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium Ma, Pingping Zha, Shenfang Shen, Xinkun Zhao, Yulan Li, Li Yang, Li Lei, Mingxing Liu, Wanqian Cell Commun Signal Research 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-1β. 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-1β in endothelium. Overexpression of NFAT5 activates NLRP3-inflammasome and increases the secretion of IL-1β in ECs partly via ROS. Chromatin immunoprecipitation assay demonstrates that NFAT5 directly binds to the promoter regions of NLRP3 and IL-1β 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12964-019-0406-7) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-20 /pmc/articles/PMC6701070/ /pubmed/31429763 http://dx.doi.org/10.1186/s12964-019-0406-7 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Ma, Pingping Zha, Shenfang Shen, Xinkun Zhao, Yulan Li, Li Yang, Li Lei, Mingxing Liu, Wanqian NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium |
title | NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium |
title_full | NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium |
title_fullStr | NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium |
title_full_unstemmed | NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium |
title_short | NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium |
title_sort | nfat5 mediates hypertonic stress-induced atherosclerosis via activating nlrp3 inflammasome in endothelium |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701070/ https://www.ncbi.nlm.nih.gov/pubmed/31429763 http://dx.doi.org/10.1186/s12964-019-0406-7 |
work_keys_str_mv | AT mapingping nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT zhashenfang nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT shenxinkun nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT zhaoyulan nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT lili nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT yangli nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT leimingxing nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium AT liuwanqian nfat5mediateshypertonicstressinducedatherosclerosisviaactivatingnlrp3inflammasomeinendothelium |