TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia

Yan, Meishan; Xu, Minghui; Li, Zhanni; An, Yao; Wang, Zelong; Li, Shuli; Chen, Yingli; Xia, Yanshi; Wang, Liqiu; Wang, Longlong; Ji, Shuting; Dong, Weijun; Shi, Jialan; Gao, Chunyan

doi:10.1016/j.bcmd.2022.102666

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…Recent data indicated that ROS‐induced lipid peroxidation activates TMEM16F in a Ca 2+ ‐independent fashion (Simões et al, 2018). Our previous studies also identified that TMEM16F is activated by an increase in ROS and lipid peroxidation caused by hyperuricemia, (Yan et al, 2022; Yu et al, 2021) however, whether hyperlipidemia enhances TMEM16F activity by ROS remains poorly understood. Consistent with previous reports, the present study observed that oxLDL enhanced intracellular Ca 2+ , ROS, and lipid peroxidation.…”

Section: Discussionmentioning

confidence: 95%

“…Exposed PS on cells enhances the procoagulant activity (PCA) by providing a catalytic surface for factor Xase (FXa) and prothrombinase complexes (Wang et al, 2022). Our previous studies have reported that uremic toxins including indole‐3‐acetic acid (IAA) and indoxyl sulfate and hyperuricemia contributed to a hypercoagulable state in vitro through PS exposure and microparticles release on erythrocytes and ECs (Gao, Ji, et al, 2015; Gao, Xie, et al, 2015; Yan et al, 2022; Yu et al, 2021). The underlying mechanism that oxLDL affects the PCA of EC during dyslipidemia has not been extensively analyzed, even though oxLDL‐induced EC injury is regarded as critical for thrombosis.…”

Section: Introductionmentioning

confidence: 99%

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OxLDL enhances procoagulant activity of endothelial cells by TMEM16F‐mediated phosphatidylserine exposure

Yan,

Wang,

et al. 2024

Cell Biology International

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Oxidized low‐density lipoprotein (oxLDL), a key component in atherosclerosis and hyperlipidemia, is a risk factor for atherothrombosis in dyslipidemia, yet its mechanism is poorly understood. In this study, we used oxLDL‐induced human aortic endothelial cells (HAECs) and high‐fat diet (HFD)‐fed mice as a hyperlipidemia model. Phosphatidylserine (PS) exposure, cytosolic Ca2+, reactive oxygen species (ROS), and lipid peroxidation were measured by flow cytometer. TMEM16F expression was detected by immunofluorescence, western blot, and reverse transcription polymerase chain reaction. Procoagulant activity (PCA) was measured by coagulation time, intrinsic/extrinsic factor Xase, and thrombin generation. We found that oxLDL‐induced PS exposure and the corresponding PCA of HAECs were increased significantly compared with control, which could be inhibited over 90% by lactadherin. Importantly, TMEM16F expression in oxLDL‐induced HAECs was upregulated by enhanced intracellular Ca2+ concentration, ROS, and lipid peroxidation, which led to PS exposure. Meanwhile, the knockdown of TMEM16F by short hairpin RNA significantly inhibited PS exposure in oxLDL‐induced HAECs. Moreover, we observed that HFD‐fed mice dramatically increased the progress of thrombus formation and accompanied upregulated TMEM16F expression by thromboelastography analysis, FeCl3‐induced carotid artery thrombosis model, and western blot. Collectively, these results demonstrate that TMEM16F‐mediated PS exposure may contribute to prothrombotic status under hyperlipidemic conditions, which may serve as a novel therapeutic target for the prevention of thrombosis in hyperlipidemia.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F‐mediated phosphatidylserine exposure

Yan,

Wang,

et al. 2024

Cell Biology International

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“…TMEM16F is a Ca 2+ -activated phospholipid scramblase located on the cell membrane, which moves phospholipids from the inner to the outer leaflet of the plasma membrane. 25 40 Recently, pieces of evidence have been provided that TMEM16F participates in cell apoptosis, ferroptosis, and pyroptosis. 52 53 54 We found increased TMEM16F expression in renal tissue of uremic rats and EC undergoing ferroptosis, which may explain the reason why phosphatidylserine externalization increased following ferroptosis in our model.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies have reported uremic toxins such as uric acid, IAA and indoxyl sulfate (IS) could significantly increase phosphatidylserine exposure of RBCs. 11,40 In the present study, we chose one of the uremic toxins IAA, we suggested that other uremic toxins including urea, creatinine, oxalic acid, uric acid and IS also play a similar role in erythrophagocytosis triggered ferroptosis of EC and followed procoagulant activity. The effect of other toxins on this process will be detected in the future.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Yan

Wang

et al. 2023

Thromb Haemost

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Although thrombosis event is the leading complication of uremia, its 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. Here, we established an in vitro co-incubation model of uremic RBC and EC as well as a uremic rat model induced by adenine. We found increased erythrophagocytosis by EC accompanied with increased reactive oxygen species (ROS), lipid peroxidation and impairment of mitochondrial using flow cytometry, confocal microscopy, and electron microscopy, indicating EC undergo ferroptosis. Further investigations showed increased proteins expression of heme oxygenase-1 (HO-1) and ferritin (FTN) and labile iron pool (LIP) accumulation in EC, which could be suppressed by deferoxamine (DFO). The negative regulators of ferroptosis GPX4 and SLC7A11 were decreased in our erythrophagocytosis model and could be enhanced by ferrostatin-1 (Fer-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 of ferroptosis. Next, we found 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. Our results indicate that erythrophagocytosis triggered ferroptosis and followed phosphatidylserine exposure of EC may play a key role in uremic thrombotic complication, which may be a promising target to prevent thrombogenesis of uremia.

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“…Human scramblase comes in three different protein families [70]. The scramblase activity of erythrocytes is performed by transmembrane protein 16F (TMEM16F, also known as anoctamin6) [71,72]. TMEM16F is a calcium-dependent homodimeric Erythrocytes as Messengers for Information and Energy Exchange between Cells DOI: http://dx.doi.org/10.5772/intechopen.108321 structure with 10 transmembrane alfa-helices and a large amino-terminal cytosolic domain in each subunit [73].…”

Section: Magnesium Cognition and The Erythrocytementioning

confidence: 99%

Erythrocytes as Messengers for Information and Energy Exchange between Cells

Johansson¹,

Falk²

2023

The Erythrocyte - A Unique Cell

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Evolution has created a hierarchy of systems for information and energy using different cells according to messages generated from DNA, RNA, and other sources. Erythrocytes are formed in high speed at about 2 × 106/s to balance dying or not working erythrocytes to maintain optimal energy and information transfer. Important information is handled by nucleotides and distribution of metal ions and phosphates when starting synthesis process. Handling of these processes needs kinases known to be magnesium-dependent. Oxygen delivered by erythrocytes is used by other cells to synthesize ATP and to increase reaction capacity. Complex signals to bone marrow balance erythroblasts before developing into reticulocytes and erythrocytes. We discuss some aspects of erythrocyte communication with other cells of the body with special focus on magnesium and selenium in this process.

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TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia

Cited by 6 publications

References 39 publications

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F‐mediated phosphatidylserine exposure

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F‐mediated phosphatidylserine exposure

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

Erythrocytes as Messengers for Information and Energy Exchange between Cells

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