Meishan Yan , Minghui Xu , Zhanni Li , Yao An , Zelong Wang , Shuli Li , Yingli Chen , Yanshi Xia , Liqiu Wang , Longlong Wang , Shuting Ji , Weijun Dong , Jialan Shi , Chunyan Gao
{"title":"TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia","authors":"Meishan Yan , Minghui Xu , Zhanni Li , Yao An , Zelong Wang , Shuli Li , Yingli Chen , Yanshi Xia , Liqiu Wang , Longlong Wang , Shuting Ji , Weijun Dong , Jialan Shi , Chunyan Gao","doi":"10.1016/j.bcmd.2022.102666","DOIUrl":null,"url":null,"abstract":"<div><p><span>The link between hyperuricemia<span><span><span> (HUA) and the risk of venous thromboembolism<span> (VTE) has been well established. However, the mechanisms of thrombus generation and the effect of HUA on </span></span>procoagulant activity (PCA) of erythrocytes remain unclear no matter in </span>uremia<span> or hyperuricemia. Here, phosphatidylserine<span> (PS) exposure, microparticles (MPs) release, cytosolic Ca</span></span></span></span><sup>2+</sup><span><span>, TMEM16F expression, reactive oxygen species<span> (ROS) and lipid peroxidation of erythrocyte were detected by flow cytometer. PCA was assessed by coagulation time, purified coagulation complex and fibrin production assays. The </span></span>fibrin formation<span><span> was observed by scanning electron microscopy (SEM). We found that PS exposure, MPs generation, TMEM16F expression and consequent PCA of erythrocyte in HUA patients significantly increased compared to those in healthy volunteers. Furthermore, high UA<span> induced PS exposure, and MPs release of erythrocyte in concentration and time-dependent manners in vitro, which enhanced the PCA of erythrocyte and was inhibited by lactadherin, a PS inhibitor. Additionally, using SEM, we also observed compact </span></span>fibrin clots<span> with highly-branched networks and thin fibers supported by red blood cells<span> (RBCs) and RBC-derived MPs (RMPs). Importantly, we demonstrated UA enhanced the production of ROS and lipid peroxidation and reduced the generation of glutathione (GSH) of erythrocyte, which enhanced TMEM16F activity and followed PS externalization and RMPs formation. Collectively, these results suggest that Ca</span></span></span></span><sup>2+</sup>-dependent TMEM16F activation may be responsible for UA-induced PS exposure and MPs release of RBC, which thereby contribute to the prothrombotic risk in HUA.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cells Molecules and Diseases","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1079979622000237","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 2
Abstract
The link between hyperuricemia (HUA) and the risk of venous thromboembolism (VTE) has been well established. However, the mechanisms of thrombus generation and the effect of HUA on procoagulant activity (PCA) of erythrocytes remain unclear no matter in uremia or hyperuricemia. Here, phosphatidylserine (PS) exposure, microparticles (MPs) release, cytosolic Ca2+, TMEM16F expression, reactive oxygen species (ROS) and lipid peroxidation of erythrocyte were detected by flow cytometer. PCA was assessed by coagulation time, purified coagulation complex and fibrin production assays. The fibrin formation was observed by scanning electron microscopy (SEM). We found that PS exposure, MPs generation, TMEM16F expression and consequent PCA of erythrocyte in HUA patients significantly increased compared to those in healthy volunteers. Furthermore, high UA induced PS exposure, and MPs release of erythrocyte in concentration and time-dependent manners in vitro, which enhanced the PCA of erythrocyte and was inhibited by lactadherin, a PS inhibitor. Additionally, using SEM, we also observed compact fibrin clots with highly-branched networks and thin fibers supported by red blood cells (RBCs) and RBC-derived MPs (RMPs). Importantly, we demonstrated UA enhanced the production of ROS and lipid peroxidation and reduced the generation of glutathione (GSH) of erythrocyte, which enhanced TMEM16F activity and followed PS externalization and RMPs formation. Collectively, these results suggest that Ca2+-dependent TMEM16F activation may be responsible for UA-induced PS exposure and MPs release of RBC, which thereby contribute to the prothrombotic risk in HUA.
期刊介绍:
Blood Cells, Molecules & Diseases emphasizes not only blood cells, but also covers the molecular basis of hematologic disease and studies of the diseases themselves. This is an invaluable resource to all those interested in the study of hematology, cell biology, immunology, and human genetics.