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Molecular Pharmacology

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Research ArticleArticle

Antithrombotic Effect of a Protein-Type I Class Snake Venom Metalloproteinase, Kistomin, Is Mediated by Affecting Glycoprotein Ib-von Willebrand Factor Interaction

Chun-Chieh Hsu, Wen-Bin Wu, Ya-Hui Chang, Heng-Lan Kuo and Tur-Fu Huang
Molecular Pharmacology October 2007, 72 (4) 984-992; DOI: https://doi.org/10.1124/mol.107.038018
Chun-Chieh Hsu
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Wen-Bin Wu
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Ya-Hui Chang
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Heng-Lan Kuo
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Tur-Fu Huang
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Abstract

Binding of von Willebrand factor (vWF) to platelet glycoprotein (GP) Ib-IX-V mediates platelet activation in the early stage of thrombus formation. Kistomin, a snake venom metalloproteinase (SVMP) purified from venom of Calloselasma rhodostoma, has been shown to inhibit vWF-induced platelet aggregation. However, its action mechanism, structure-function relationship, and in vivo antithrombotic effects are still largely unknown. In the present study, cDNA encoding kistomin precursor was cloned and revealed that kistomin is a P-I class SVMP with only a proteinase domain. Further analysis indicated that kistomin specifically inhibited vWF-induced platelet aggregation through binding and cleavage of platelet GPIbα and vWF. Cleavage of platelet GPIbα by kistomin resulted in release of 45- and 130-kDa soluble fragments, indicating that kistomin cleaves GPIbα at two distinct sites. In parallel, cleavage of vWF by kistomin also resulted in the formation of low-molecular-mass multimers of vWF. In ex vivo and in vivo studies, kistomin cleaved platelet GPIbα in whole blood. Moreover, GPIbα agonist-induced platelet aggregation ex vivo was inhibited, and tail-bleeding time was prolonged in mice administered kistomin intravenously. Kistomin's in vivo antithrombotic effect was also evidenced by prolonging the occlusion time in mesenteric microvessels of mice. In conclusion, kistomin, a P-I class metalloproteinase, has a relative specificity for GPIbα and vWF and its proteolytic activity on GPIbα-vWF is responsible for its antithrombotic activity both in vitro and in vivo. Kistomin can be useful as a tool for studying metalloproteinase-substrate interactions and has a potential being developed as an antithrombotic agent.

Footnotes

  • This work was financially supported by National Science Council grant NSC95-2320-B002-045, Taiwan.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.038018.

  • ABBREVIATIONS: vWF, von Willebrand factor; GP, glycoprotein; SVMP, snake venom metalloproteinase; mAb, monoclonal antibody; FITC, fluorescein isothiocyanate; PVDF, polyvinylidene difluoride; PCR, polymerase chain reaction; PRP, platelet-rich plasma; PS, platelet suspension; RT, room temperature; PBS, phosphate-buffered saline; P-I–IV, protein-types I–IV.

    • Received May 10, 2007.
    • Accepted July 3, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (4)
Molecular Pharmacology
Vol. 72, Issue 4
1 Oct 2007
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Research ArticleArticle

Antithrombotic Effect of a Protein-Type I Class Snake Venom Metalloproteinase, Kistomin, Is Mediated by Affecting Glycoprotein Ib-von Willebrand Factor Interaction

Chun-Chieh Hsu, Wen-Bin Wu, Ya-Hui Chang, Heng-Lan Kuo and Tur-Fu Huang
Molecular Pharmacology October 1, 2007, 72 (4) 984-992; DOI: https://doi.org/10.1124/mol.107.038018

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Research ArticleArticle

Antithrombotic Effect of a Protein-Type I Class Snake Venom Metalloproteinase, Kistomin, Is Mediated by Affecting Glycoprotein Ib-von Willebrand Factor Interaction

Chun-Chieh Hsu, Wen-Bin Wu, Ya-Hui Chang, Heng-Lan Kuo and Tur-Fu Huang
Molecular Pharmacology October 1, 2007, 72 (4) 984-992; DOI: https://doi.org/10.1124/mol.107.038018
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