Research Paper Advance Articles
NFAT5 directs hyperosmotic stress-induced fibrin deposition and macrophage infiltration via PAI-1 in endothelium
- 1 Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, China
- 2 Chongqing University Cancer Hospital, Department of Radiotherapy, Chongqing University, Chongqing 400044, China
- 3 School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China
- 4 Obstetrics and Gynecology Department, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
Received: June 1, 2020 Accepted: October 31, 2020 Published: December 19, 2020https://doi.org/10.18632/aging.202330
How to Cite
Copyright: © 2021 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Although stress can significantly promote atherosclerosis, the underlying mechanisms are still not completely understood. Here we successfully unveiled that high salt-induced nuclear factor of activated T cells 5 (NFAT5) control the endothelial-dependent fibrinolytic activity and the inflammatory adhesion-related molecules expression through regulation of plasminogen activator inhibitor-1 (PAI-1). We first observed that high salt diets instigated the expression of NFAT5 and PAI-1 in the endothelium which brought about the fibrin deposition and macrophage infiltration in the atherosclerotic arteries of ApoE-/- mice. Overexpression of NFAT5 increased PAI-1-mediated antifibrinolytic activity and activated inflammatory adhesion-related genes in endothelial cells. Knockdown of NFAT5 by siRNA inhibited the expression of PAI-1, antifibrinolytic and adhesive molecules. Moreover, chromatin immunoprecipitation assay demonstrated that high salt intake significantly promoted the binding of NFAT5 to PAI-1 promoter (TGGAATTATTT) in endothelial cells. Our study identified that NFAT5 has great potential to activate the PAI-1-mediated fibrinolytic dysfunction and inflammatory cell adhesion, thus promoting high salt-induced atherosclerosis disease.
AS: atherosclerosis; ECs: endothelial cells; HS: high salt; PAI-1: Plasminogen activator inhibitor-1; PLAU: urokinase plasminogen activator; PLAT: tissue plasminogen activator; NFAT5: nuclear factor of activated T cells 5; vWF: von Willebrand factor; ApoE-/- mice: apolipoprotein E-deficient mice; AA: aortic arch; TA: thoracic aorta; HUVECs: human umbilical vein endothelial cells; ICAM-1: intercellular cell adhesion molecule-1; MCP-1: monocyte chemoattractant protein-1; VCAM-1: vascular cell adhesion molecule-1; PLG: plasminogen; ChIP: chromatin immunoprecipitation; ORE: osmotic response element; β-ECGF: β-Endothelial cell growth factor.