Dataset Information

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 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?.

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? in endothelium. Overexpression of NFAT5 activates NLRP3-inflammasome and increases the secretion of IL-1? in ECs partly via ROS. Chromatin immunoprecipitation assay demonstrates that NFAT5 directly binds to the promoter regions of NLRP3 and IL-1? 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.

SUBMITTER: Ma P

PROVIDER: S-EPMC6701070 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium.

Ma Pingping P Zha Shenfang S Shen Xinkun X Zhao Yulan Y Li Li L Yang Li L Lei Mingxing M Liu Wanqian W

Cell communication and signaling : CCS 20190820 1

<h4>Background</h4>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.<h4>Methods</h4>Atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice ...[more]

PMID: 31429763

Similar Datasets

Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

Project description:ContextCardiomyocyte hypertrophy due to hemodynamic overload eventually leads to heart failure. Hirudin has been widely used in the treatment of cardiovascular diseases and NLRP3 inflammasome was proven to induce cardiomyocyte pyroptosis. However, the mechanism by which it inhibits cardiomyocyte hypertrophy remains unclear.ObjectiveTo explore the mechanism of hirudin inhibiting cardiomyocyte hypertrophy based on NLRP3 inflammasome activation and mitophagy.Materials & methods1 μM AngII was used for cardiac hypertrophy modeling in H9C2 cells, and cell viability was quantified by CCK-8 assay to screen the appropriate action concentrations of hirudin. After that, we cultured AngII induced-H9C2 cells for 24 h with 0, 0.3, 0.6, and 1.2 mM hirudin, respectively. Next, we marked H9C2 cells with phalloidine and observed them using fluorescence microscope. IL-1β, IL-18, IL-6, TNF-α, ANP, BNP, β-MHC, and mtDNA were analyzed by qRT-PCR; ROS were quantified by Flow cytometry; SOD, MDA, and GSH-Px were detected by ELISA; and proteins including NLRP3, ASC, caspase-1, pro-caspase-1, IL-1β, IL-18, PINK-1, Parkin, beclin-1, LC3-Ⅰ, LC3-Ⅱ, p62, were quantified by western blotting.ResultsIt was discovered that hirudin reduced the superficial area of AngII-induced H9C2 cells and inhibited the AngII-induced up-regulation of ANP, BNP, and β-MHC. Besides, hirudin down-regulated the expressions of NLRP3 inflammasome-related cytokines, containing IL-1β, IL-18, IL-6, TNF-α. It also down-regulated the expression of mtDNA and ROS, decreased the expression levels of NLRP3 inflammasome activation related proteins, including NLRP3, ASC, caspase-1, pro-caspase-1, IL-1β, IL-18; and increased the expressions of PINK-1, Parkin, beclin-1, LC3-Ⅱ/LC3-Ⅰ, p62 in AngII-induced H9C2 cells.DiscussionHirudin promoted the process of mitophagy, inhibited the development of inflammation and oxidative stress, and inhibited the activation of the NLRP3 inflammasome and the PINK-1/Parkin pathway.ConclusionHirudin has the activity to suppress cardiac hypertrophy may benefit from the inhibition of NLRP3 inflammasome and activating of PINK-1/Parkin related-mitophagy.

Dataset Information

NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium.

Background

Methods

Results

Conclusions

Publications

NFAT5 mediates hypertonic stress-induced atherosclerosis via activating NLRP3 inflammasome in endothelium.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets