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Research Paper|Volume 13, Issue 6|pp 8628—8642

Activation of ATF4 triggers trabecular meshwork cell dysfunction and apoptosis in POAG

Ying Ying2, Ran Xue1, Yangfan Yang1, Sarah X Zhang4,5,6, Hui Xiao1, Huazhang Zhu2, Jingming Li3, Guo Chen1, Yiming Ye1, Minbin Yu1, Xing Liu1, Yimin Zhong1
  • 1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
  • 2Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, Guangdong, China
  • 3Department of Ophthalmology, The First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi an, Shanxi, China
  • 4Department of Ophthalmology and Ross Eye Institute, University at Buffalo, State University of New York, Buffalo, NY 14209, USA
  • 5SUNY Eye Institute, State University of New York, New York, NY 10036, USA
  • 6Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, NY 14203, USA
* Equal contribution
Received: August 10, 2020Accepted: February 1, 2021Published: March 10, 2021
https://doi.org/10.18632/aging.202677

Copyright: © 2021 Ying 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

Primary open angle glaucoma (POAG) is the leading cause of irreversible blindness. Dysfunction of the trabecular meshwork (TM), resulting in decreased outflow of aqueous humor and increased intraocular pressure (IOP), plays an important role in the pathogenesis of POAG. However, the underlying mechanisms still remain unclear. In this study, we demonstrated that the eIF2-α/ATF4/CHOP branch of unfolded protein response (UPR) was activated in human trabecular meshwork cells (HTMCs) upon tert-butyl hydroperoxide (TBHP) exposure. Inhibition of ATF4 ameliorated TBHP-induced apoptosis and inflammatory cytokine production, while ectopic expression of ATF4 increased the expression of endothelial leukocyte adhesion molecule (ELAM)-1 and IL-8 in HTMCs. Furthermore, we found that ATF4 inhibition reduced tunicamycin-induced caspase-3 activation, ROS production, ELAM-1 expression, and HTMCs phagocytosis impairment. By an in vivo study in mice, we showed that overexpression of ATF4 in the TM induced C/EBP homologous protein (CHOP) expression and TM cells apoptosis, contributing to inflammatory cytokine production, and probably IOP elevation. More importantly, upregulation of ATF4 and CHOP, and colocalization of ATF4 with ELAM-1 were found in the TM of POAG patients. These results suggest that ATF4 is a critical mediator of oxidative stress and ER stress-induced TM cell dysfunction and apoptosis in POAG.