ARHGEF10 knockout inhibits platelet aggregation and protects mice from thrombus formation

D. H. Lu, C. C. Hsu, S. W. Huang, H. J. Tu, T. F. Huang, H. C. Liou, H. M. Liao, C. H. Chen, W. M. Fu, S. S.F. Gau

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5 Citations (Scopus)

Abstract

Essentials ARHGEF10 single-nucleotide polymorphism provides risk of ischemic and atherothrombotic stroke. The role of ARHGEF10 in platelet function was examined using ARHGEF10 knockout mice. ARHGEF10 deficiency inhibits platelet function and arterial thrombus formation. ARHGEF10 knockout protects mice from stroke-induced infarction. Summary: Background ARHGEF10, a member of the Rho guanine nucleotide exchange factor (GEF) family, stimulates Rho GTPases. Rho GTPases have been reported to regulate a variety of cellular behaviors, such as cell polarity, cytoskeletal organization, and gene transcription. ARHGEF10 single-nucleotide polymorphisms are linked to the risk of ischemic stroke. However, the role of ARHGEF10 in platelet function remains unknown. Objective To examine the role of ARHGEF10 in platelet function. Methods ARHGEF10−/−were generated. We examined the in vitro and in vivo effects of ARHGEF10 knockout on platelet function and arterial thrombosis formation. Results ARHGEF10−/− mice had normal platelet counts, but showed altered aggregation in response to thrombin, collagen, ADP, protease-activated receptor-4 peptide, and U46619 stimulation. ARHGEF10 knockout influenced platelet spreading on fibrinogen-coated surfaces, and caused the platelets to show less lamellipodia-like extension than wild-type platelets. ARHGEF10 knockout also inhibited platelet clot retraction induced by thrombin stimulation. ARHGEF10 knockout resulted in prolonged tail bleeding time and inhibited the stable thrombus formation induced by FeCl3 in the carotid artery. Conclusions ARHGEF10 serves as an important regulator in platelet shape change, spreading, and aggregation. Moreover, ARHGEF10 also plays an important role in arterial thrombosis formation.

Original languageEnglish
Pages (from-to)2053-2064
Number of pages12
JournalJournal of Thrombosis and Haemostasis
Volume15
Issue number10
DOIs
Publication statusPublished - Oct 1 2017
Externally publishedYes

Keywords

  • ARHGEF10 knockout mice
  • guanine nucleotide exchange factors
  • platelet function
  • Rho guanine nucleotide exchange factor
  • thombosis

ASJC Scopus subject areas

  • Hematology

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  • Cite this

    Lu, D. H., Hsu, C. C., Huang, S. W., Tu, H. J., Huang, T. F., Liou, H. C., Liao, H. M., Chen, C. H., Fu, W. M., & Gau, S. S. F. (2017). ARHGEF10 knockout inhibits platelet aggregation and protects mice from thrombus formation. Journal of Thrombosis and Haemostasis, 15(10), 2053-2064. https://doi.org/10.1111/jth.13799