Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2021; 12(2): 124-137
Published online Feb 15, 2021. doi: 10.4239/wjd.v12.i2.124
Role of ferroptosis in the process of diabetes-induced endothelial dysfunction
Er-Fei Luo, Hong-Xia Li, Yu-Han Qin, Yong Qiao, Gao-Liang Yan, Yu-Yu Yao, Lin-Qing Li, Jian-Tong Hou, Cheng-Chun Tang, Dong Wang
Er-Fei Luo, Hong-Xia Li, Yu-Han Qin, Lin-Qing Li, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
Yong Qiao, Gao-Liang Yan, Yu-Yu Yao, Jian-Tong Hou, Cheng-Chun Tang, Dong Wang, Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
Author contributions: Luo EF, Li HX, Wang D and Tang CC conceived and designed the experiments; Luo EF, Li HX, Qin YH and Li LQ performed the experiments and data analyses and wrote the manuscript; Yan GL, Qiao Y and Hou JT contributed to the quality control of data and algorithms; Yao YY helped perform the data analysis and manuscript revision with constructive discussions; all authors read and approved the final manuscript. Luo EF and Li HX contributed equally to this work and should be considered co-first authors.
Supported by National Natural Science Foundation of China, No. 81800244 and No. 81670237.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of Zhongda Hospital, Affiliated to Southeast University (Approval No. 2018ZDKYSB047), and followed the principles of the Declaration of Helsinki.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Southeast University (Protocol No. 20190304012).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dong Wang, PhD, Doctor, Department of Cardiology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Gulou District, Nanjing 210009, Jiangsu Province, China. wangdong_seu@163.com
Received: June 28, 2020
Peer-review started: June 28, 2020
First decision: October 21, 2020
Revised: November 30, 2020
Accepted: December 11, 2020
Article in press: December 11, 2020
Published online: February 15, 2021
Abstract
BACKGROUND

Endothelial dysfunction, a hallmark of diabetes, is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications. However, the underlying mechanisms are still not fully understood. Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases, the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.

AIM

To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.

METHODS

Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG), interleukin-1β (IL-1β), and ferroptosis inhibitor, and then the cell viability, reactive oxygen species (ROS), and ferroptosis-related marker protein were tested. To further determine whether the p53-xCT (the substrate-specific subunit of system Xc-)-glutathione (GSH) axis is involved in HG and IL-1β induced ferroptosis, HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β. Cell viability, ROS, and ferroptosis-related marker protein were then assessed. In addition, we detected the xCT and p53 expression in the aorta of db/db mice.

RESULTS

It was found that HG and IL-1β induced ferroptosis in HUVECs, as evidenced by the protective effect of the ferroptosis inhibitors, Deferoxamine and ferrostatin-1, resulting in increased lipid ROS and decreased cell viability. Mechanistically, activation of the p53-xCT-GSH axis induced by HG and IL-1β enhanced ferroptosis in HUVECs. In addition, a decrease in xCT and the presence of de-endothelialized areas were observed in the aortic endothelium of db/db mice.

CONCLUSION

Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.

Keywords: Diabetes mellitus, Endothelial dysfunction, Ferroptosis, Reactive oxygen species, p53, Glutathione

Core Tip: Endothelial dysfunction is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications. Ferroptosis is characterized by the accumulation of iron-induced lipid reactive oxygen species and depletion of plasma membrane unsaturated fatty acids. Our findings demonstrated that ferroptosis is involved in endothelial dysfunction and the p53- xCT (the substrate-specific subunit of system Xc-)-glutathione axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction. These results provide important insights as inhibiting activation of the p53-xCT-glutathione axis and ferroptosis could attenuate diabetes-induced endothelial dysfunction and may be a novel strategy for the treatment of vascular complications in diabetes mellitus.