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CC BY-NC-ND 4.0 · Thromb Haemost 2023; 123(12): 1116-1128
DOI: 10.1055/a-2117-7890
Coagulation and Fibrinolysis

Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia

Zhanni Li
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Meishan Yan
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Zelong Wang
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Yao An
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Xinyu Wei
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Tingting Li
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Minghui Xu
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Yanshi Xia
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
,
Liqiu Wang
2   Department of Clinical Laboratory, The Fifth Hospital, Harbin Medical University, Daqing, China
,
Chunyan Gao
1   Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
› Author Affiliations
Funding This work was supported by the National Natural Science Foundation of China (82070140 and 82270134), Marshal Initiative Funding (HMUMIF-22005), PhD Fund of Harbin Medical University-Daqing (XQBSQDJ201902), Natural Science Foundation of Heilongjiang Province (LH2020H0299), Heilongjiang Postdoctoral Science Foundation (LBHQ19127), Yu Weihan Foundation of Harbin Medical University (31021180167 and DQYWH201801), and Center of Diagnosis and Treatment of Disease in Cold Place, Harbin Medical University (CXZX-ZXKT01).
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Abstract

Background Although thrombosis events are the leading complication of uremia, their mechanism is largely unknown. The interaction between endothelial cells (ECs) and red blood cells (RBCs) in uremic solutes and its prothrombotic role need to be investigated.

Methods and Results Here, we established an in vitro co-incubation model of uremic RBC and EC as well as a uremic rat model induced by adenine. Using flow cytometry, confocal microscopy, and electron microscopy, we found increased erythrophagocytosis by EC accompanied by increased reactive oxygen species, lipid peroxidation, and impairment of mitochondria, indicating that ECs undergo ferroptosis. Further investigations showed increased proteins' expression of heme oxygenase-1 and ferritin and labile iron pool accumulation in EC, which could be suppressed by deferoxamine (DFO). The ferroptosis-negative regulators glutathione peroxidase 4 and SLC7A11 were decreased in our erythrophagocytosis model and could be enhanced by ferrostatin-1 or DFO. In vivo, we observed that vascular EC phagocytosed RBC and underwent ferroptosis in the kidney of the uremic rat, which could be inhibited by blocking the phagocytic pathway or inhibiting ferroptosis. Next, we found that the high tendency of thrombus formation was accompanied by erythrophagocytosis-induced ferroptosis in vitro and in vivo. Importantly, we further revealed that upregulated TMEM16F expression mediated phosphatidylserine externalization on ferroptotic EC, which contributed to a uremia-associated hypercoagulable state.

Conclusion Our results indicate that erythrophagocytosis-triggered ferroptosis followed by phosphatidylserine exposure of EC may play a key role in uremic thrombotic complications, which may be a promising target to prevent thrombogenesis of uremia.

Keywords

erythrophagocytosis - ferroptosis - endothelial cell - thrombosis - uremia

Authors' Contribution

Z.L. performed the experiments, analyzed the data, and edited the manuscript; Z.W., M.Y., Y.A., and L.W. performed the experiments and analyzed the data; M.X., Y.X., X.W., and T.L. contributed to the study design and commented on the manuscript; C.G. designed and conducted the research, analyzed, and interpreted the data, and wrote the manuscript.


Supplementary Material



Publication History

Received: 28 September 2022

Accepted: 12 June 2023

Accepted Manuscript online:
26 June 2023

Article published online:
03 August 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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