Nicked β2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property

Hisako Nakagawa, Shinsuke Yasuda, Eiji Matsuura, Kazuko Kobayashi, Masahiro Ieko, Hiroshi Kataoka, Tetsuya Horita, Tatsuya Atsumi, Takao Koike

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Angiostatin was first discovered as a plasminogen fragment with antitumor/antiangiogenic property. One of the angiostatin isoforms, that is, angiostatin 4.5 (AS4.5), consisting of plasminogen kringle 1 to 4 and a most part of kringle 5, is produced by autoproteolysis and present in human plasma. β2-glycoprotein I (β2GPI) is proteolytically cleaved by plasmin in its domain V (nicked β2GPI), resulting in binding to plasminogen. Antiangiogenic properties have been recently reported in nicked β2GPI as well as in intact β2GPI at higher concentrations. In the present study, we found significant binding of nicked β2GPI to AS4.5 (KD = 3.27 × 106 M-1). Via this binding, nicked β2GPI attenuates the antiangiogenic functions of AS4.5 in the proliferation of arterial/venous endothelial cells, in the extracellular matrix invasion and the tube formation of venous endothelial cells, and in vivo angiogenesis. In contrast, intact β2GPI does not bind to AS4.5 or inhibit its antiangiogenic activity. Thus, nicked β2GPI exerts dual effects on angiogenesis, that is, nicked β2GPI promotes angiogenesis in the presence of AS4.5, whereas nicked β2GPI inhibits angiogenesis at concentrations high enough to neutralize AS4.5. Our data suggest that plasmin-nicked β2GPI promotes angiogenesis by interacting with plasmin-generated AS4.5 in sites of increased fibrinolysis such as thrombus.

Original languageEnglish
Pages (from-to)2553-2559
Number of pages7
JournalBlood
Volume114
Issue number12
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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