Res Pract Thromb Haemost, 2025 Feb 27;9(2):102706. doi: 10.1016/j.rpth.2025.102706. eCollection 2025 Feb

题目： 

Thiol isomerase ERp18 enhances platelet activation and arterial thrombosis

作者：

Chao He# 1 2, Aizhen Yang# 1, Keyu Lv# 3, Yuxin Zhang 2, Zhenzhen Zhao 1, Yi Lu 4, Chao Fang 3, Yue Han 5, Depei Wu 5, Miao Jiang 1, Jingyu Zhang 2, Yi Wu 1 2

单位：

1 Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.

2 Department of Hematology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Hematology, Shijiazhuang, China.

3 Department of Pharmacology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.

4 Hunan Sinozex Biosciences Co, Ltd, Changsha, China.

5 Department of Hematology, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, China.

^#Contributed equally.

摘要：

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 α_IIbβ₃.

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 α_IIbβ₃ 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 α_IIbβ₃. Moreover, the ERp18 protein promoted the binding of integrin α_IIbβ₃ to fibrinogen and platelet aggregation. Furthermore, the recombinant ERp18 protein exhibited reductase activity and cleaved integrin α_IIbβ₃ disulfides.

Conclusion: ERp18 participates in platelet activation and thrombosis. Its function is, at least in part, through the regulation of integrin α_IIbβ₃ function. This finding expands our understanding of the role of thiol isomerases in the redox regulation of thrombosis and platelet function.