4.6 Article

Impaired Platelet Function in Sept8-Deficient Mice In Vitro

Journal

THROMBOSIS AND HAEMOSTASIS
Volume 121, Issue 4, Pages 484-494

Publisher

GEORG THIEME VERLAG KG
DOI: 10.1055/s-0040-1718733

Keywords

platelets; septins; exocytosis; glycoprotein VI; coagulation

Funding

  1. Deutsche Forschungsgemeinschaft DFG [ZI 486/4-1, ZI 486/8-1]
  2. German Federal Ministry of Education and Research [BMBF 01EO1503]

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This study demonstrated the crucial role of Sept8 in platelet function, particularly in integrin activation, alpha-granule release, aggregation, and thrombin generation. Sept8 deficiency led to defects in these processes, highlighting its importance in primary and secondary hemostasis.
Septins (Septs) are a widely expressed protein family of 13 mammalian members, recognized as a unique component of the cytoskeleton. In human platelets, we previously described that SEPT4 and SEPT8 are localized surrounding alpha -granules and move to the platelet surface after activation, indicating a possible role in platelet physiology. In this study, we investigated the impact of Sept8 on platelet function in vitro using Sept8-deficient mouse platelets. Deletion of Sept8 in mouse platelets caused a pronounced defect in activation of the fibrinogen receptor integrin alpha (IIb) beta (3,) alpha -granule exocytosis, and aggregation, especially in response to the glycoprotein VI agonist convulxin. In contrast, delta -granule and lysosome exocytosis of Sept8-deficient platelets was comparable to wild-type platelets. Sept8-deficient platelet binding to immobilized fibrinogen under static conditions was diminished and spreading delayed. The procoagulant activity of Sept8-deficient platelets was reduced in response to convulxin as determined by lactadherin binding. Also thrombin generation was decreased relative to controls. Thus, Sept8 is required for efficient integrin alpha (IIb) beta (3) activation, alpha -granule release, platelet aggregation, and contributes to platelet-dependent thrombin generation. These results revealed Sept8 as a modulator of distinct platelet functions involved in primary and secondary hemostatic processes.

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