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

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.

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.

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.

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.