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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Georg Thieme Verlag KG
2023
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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. |
format | Online Article Text |
id | pubmed-10686749 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Georg Thieme Verlag KG |
record_format | MEDLINE/PubMed |
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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