Thiol isomerase ERp18 enhances platelet activation and arterial thrombosis

IF 3.4 3区 医学 Q2 HEMATOLOGY
Chao He , Aizhen Yang , Keyu Lv , Yuxin Zhang , Zhenzhen Zhao , Yi Lu , Chao Fang , Yue Han , Depei Wu , Miao Jiang , Jingyu Zhang , Yi Wu
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Abstract

Background

Thiol isomerases regulate the thiol-disulfide exchange of functional proteins in cells. Using genetically modified mouse models and inhibitors, we and others demonstrated that 7 thiol isomerases (ERp57, protein diisulfide isomerase, ERp72, ERp46, ERp5, TMX4, and TMX1) participate in thrombosis. There are 21 thiol isomerases in mammals, but whether other enzymes of this family also contribute to thrombosis remains unknown.

Objectives

Investigate whether and how ERp18 participates in arterial thrombosis.

Methods

ERp18 knockout mice and arterial thrombosis models were used to determine the role of ERp18 in thrombosis. Platelets from ERp18 knockout mice were used to detect aggregation, activation, spreading, and clot retraction. Finally, flow cytometry and immunoprecipitation were used to detect the binding between ERp18 and αIIbβ3.

Results

The mice lacking ERp18 exhibited a prolonged tail bleeding time and decreased platelet thrombus formation in FeCl3-induced carotid arterial injury and laser-induced cremaster artery injury models. ERp18 deficiency inhibited platelet aggregation, adenosine triphosphate release, integrin αIIbβ3 activation, P-selectin expression, platelet adhesion, as well as clot retraction. Flow cytometry and coimmunoprecipitation analyses revealed that ERp18 binds to the platelet surface via interaction with integrin αIIbβ3. Moreover, the ERp18 protein promoted the binding of integrin αIIbβ3 to fibrinogen and platelet aggregation. Furthermore, the recombinant ERp18 protein exhibited reductase activity and cleaved integrin αIIbβ3 disulfides.

Conclusion

ERp18 participates in platelet activation and thrombosis. Its function is, at least in part, through the regulation of integrin αIIbβ3 function. This finding expands our understanding of the role of thiol isomerases in the redox regulation of thrombosis and platelet function.
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来源期刊
CiteScore
5.60
自引率
13.00%
发文量
212
审稿时长
7 weeks
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