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Research Paper|Volume 13, Issue 3|pp 3661—3679

NFAT5 directs hyperosmotic stress-induced fibrin deposition and macrophage infiltration via PAI-1 in endothelium

Pingping Ma1,3, Guang Li2, Xiaorui Jiang1, Xinkun Shen3, Hong Li4, Li Yang1, Wanqian Liu1
  • 1Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing 400044, China
  • 2Chongqing University Cancer Hospital, Department of Radiotherapy, Chongqing University, Chongqing 400044, China
  • 3School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou 325027, China
  • 4Obstetrics and Gynecology Department, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
* Equal contribution
Received: June 1, 2020Accepted: October 31, 2020Published: December 19, 2020
https://doi.org/10.18632/aging.202330

Copyright: © 2020 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.

Abstract

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.