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

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...

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Autores principales: Li, Zhanni, Yan, Meishan, Wang, Zelong, An, Yao, Wei, Xinyu, Li, Tingting, Xu, Minghui, Xia, Yanshi, Wang, Liqiu, Gao, Chunyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Georg Thieme Verlag KG 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686749/
https://www.ncbi.nlm.nih.gov/pubmed/37364609
http://dx.doi.org/10.1055/a-2117-7890
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author Li, Zhanni
Yan, Meishan
Wang, Zelong
An, Yao
Wei, Xinyu
Li, Tingting
Xu, Minghui
Xia, Yanshi
Wang, Liqiu
Gao, Chunyan
author_facet Li, Zhanni
Yan, Meishan
Wang, Zelong
An, Yao
Wei, Xinyu
Li, Tingting
Xu, Minghui
Xia, Yanshi
Wang, Liqiu
Gao, Chunyan
author_sort Li, Zhanni
collection PubMed
description 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.
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spelling pubmed-106867492023-11-30 Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia Li, Zhanni Yan, Meishan Wang, Zelong An, Yao Wei, Xinyu Li, Tingting Xu, Minghui Xia, Yanshi Wang, Liqiu Gao, Chunyan Thromb Haemost 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. Georg Thieme Verlag KG 2023-08-03 /pmc/articles/PMC10686749/ /pubmed/37364609 http://dx.doi.org/10.1055/a-2117-7890 Text en 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/ ) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.
spellingShingle Li, Zhanni
Yan, Meishan
Wang, Zelong
An, Yao
Wei, Xinyu
Li, Tingting
Xu, Minghui
Xia, Yanshi
Wang, Liqiu
Gao, Chunyan
Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia
title Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia
title_full Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia
title_fullStr Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia
title_full_unstemmed Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia
title_short Ferroptosis of Endothelial Cells Triggered by Erythrophagocytosis Contributes to Thrombogenesis in Uremia
title_sort ferroptosis of endothelial cells triggered by erythrophagocytosis contributes to thrombogenesis in uremia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10686749/
https://www.ncbi.nlm.nih.gov/pubmed/37364609
http://dx.doi.org/10.1055/a-2117-7890
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