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

Zhanni Li; Meishan Yan; Zelong Wang; Yao An; Xinyu Wei; Tingting Li; Minghui Xu; Yanshi Xia; Liqiu Wang; Chunyan Gao

doi:10.1055/a-2117-7890

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

Autor*innen

Zhanni Li

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Meishan Yan

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Zelong Wang

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Yao An

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Xinyu Wei

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Tingting Li

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Minghui Xu

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Yanshi Xia

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China
Liqiu Wang

²Department of Clinical Laboratory, The Fifth Hospital, Harbin Medical University, Daqing, China
Chunyan Gao

¹Department of Medical Laboratory Science and Technology, Harbin Medical University-Daqing, Daqing, China

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

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Referenzen

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