Research Paper Volume 12, Issue 13 pp 12740—12749

PAK4 suppresses TNF-induced release of endothelial microparticles in HUVECs cells

Shouqin Zhang1, , Yingjie Yin2, , Congye Li1, , Yi Zhao1, , Qixing Wang1, , Xiangyu Zhang1, ,

  • 1 Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Jing’an, Shanghai 200072, China
  • 2 Department of Critical Care Medicine, The Affiliated Hospital of Medical School of Ningbo, Jiangbei District, Ningbo 315000, Zhejiang province, China

Received: July 3, 2019       Accepted: April 7, 2020      

https://doi.org/10.18632/aging.103173
How to Cite

Copyright © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Tumor necrosis factor-α (TNF) is a pro-inflammatory cytokine upregulated in many inflammatory diseases, and a potent inducer of endothelial cell-derived microparticle (EMP) formation. In this study, we identified the protein kinase PAK4 as a key regulator of the TNF-induced EMP release from human umbilical vein endothelial cells (HUVECs). TNF induces dose- and time-dependent EMP release and downregulation of PAK4 and upstream cdc42 in HUVECs. PAK4 suppression or inhibition of its kinase activity increases TNF-induced EMP release and apoptosis in HUVECs, while PAK4 overexpression reduces EMP release and apoptosis in TNF-stimulated cells. Collectively, these data indicate that PAK4 suppresses TNF-induced EMP generation occurring during apoptosis, and suggest that modulation of PAK4 activity may represent a novel approach to suppress the TNF-induced EMP levels in pro-inflammatory disorders and other pathological conditions.

Abbreviations

TNF: Tumor necrosis factor-α; EMP: Endothelial cell-derived microparticle; HUVECs: Human umbilical vein endothelial cells; PAK4: p21-activated kinase 4; siRNA: Small interfering RNA; MP: Microparticle; sTNFR1: soluble TNF receptor 1.