NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium
Abstract 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 expre...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-08-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | http://link.springer.com/article/10.1186/s12964-019-0406-7 |
| _version_ | 1818335508892221440 |
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| author | Pingping Ma Shenfang Zha Xinkun Shen Yulan Zhao Li Li Li Yang Mingxing Lei Wanqian Liu |
| author_facet | Pingping Ma Shenfang Zha Xinkun Shen Yulan Zhao Li Li Li Yang Mingxing Lei Wanqian Liu |
| author_sort | Pingping Ma |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-13T14:24:33Z |
| format | Article |
| id | doaj.art-283f1ea0c46c446fbf4e2ccc8dba6011 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-13T14:24:33Z |
| publishDate | 2019-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-283f1ea0c46c446fbf4e2ccc8dba60112022-12-21T23:41:59ZengBMCCell Communication and Signaling1478-811X2019-08-0117111310.1186/s12964-019-0406-7NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endotheliumPingping Ma0Shenfang Zha1Xinkun Shen2Yulan Zhao3Li Li4Li Yang5Mingxing Lei6Wanqian Liu7Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityKey Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityKey Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityKey Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityKey Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityKey Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityIntegrative Stem Cell Center, China Medical University Hospital, China Medical UniversityKey Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing UniversityAbstract 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.http://link.springer.com/article/10.1186/s12964-019-0406-7AtherosclerosisNLRP3 inflammasomeNFAT5Hypertonic stressEndothelium |
| spellingShingle | Pingping Ma Shenfang Zha Xinkun Shen Yulan Zhao Li Li Li Yang Mingxing Lei Wanqian Liu NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium Cell Communication and Signaling Atherosclerosis NLRP3 inflammasome NFAT5 Hypertonic stress 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 | Atherosclerosis NLRP3 inflammasome NFAT5 Hypertonic stress Endothelium |
| url | http://link.springer.com/article/10.1186/s12964-019-0406-7 |
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