Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site

Jin Hyung Ahn, Ho Jeong Lee, Eun Kyoung Lee, Hyun Kyung Yu, Tae Ho Lee, Yeup Yoon, Sun Jin Kim, Jang Seong Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Many proteins in the fibrinolysis pathway contain antiangiogenic kringle domains. Owing to the high degree of homology between kringle domains, there has been a safety concern that antiangiogenic kringles could interact with common kringle proteins during fibrinolysis leading to adverse effects in vivo. To address this issue, we investigated the effects of several antiangiogenic kringle proteins including angiostatin, apolipoprotein(a) kringles IV 9-IV10-V (LK68), apolipoprotein(a) kringle V (rhLK8) and a derivative of rhLK8 mutated to produce a functional lysine-binding site (Lys-rhLK8) on the entire fibrinolytic process in vitro and analyzed the role of lysine binding. Angiostatin, LK68 and Lys-rhLK8 increased clot lysis time in a dose-dependent manner, inhibited tissue-type plasminogen activator-mediated plasminogen activation on a thrombin-modified fibrinogen (TMF) surface, showed binding to TMF and significantly decreased the amount of plasminogen bound to TMF. The inhibition of fibrinolysis by these proteins appears to be dependent on their functional lysine-binding sites. However, rhLK8 had no effect on these processes owing to an inability to bind lysine. Collectively, these results indicate that antiangiogenic kringles without lysine binding sites might be safer with respect to physiological fibrinolysis than lysinebinding antiangiogenic kringles. However, the clinical significance of these findings will require further validation in vivo.

Original languageEnglish
Pages (from-to)347-356
Number of pages10
JournalBiological Chemistry
Volume392
Issue number4
DOIs
Publication statusPublished - 2011 Apr 1

Fingerprint

Kringles
Apoprotein(a)
Plasminogen
Fibrinolysis
Lysine
Binding Sites
Angiostatins
Thrombin
Fibrinogen
Proteins
Tissue Plasminogen Activator
Fibrin Clot Lysis Time
Chemical activation
Derivatives
Safety

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Ahn, Jin Hyung ; Lee, Ho Jeong ; Lee, Eun Kyoung ; Yu, Hyun Kyung ; Lee, Tae Ho ; Yoon, Yeup ; Kim, Sun Jin ; Kim, Jang Seong. / Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site. In: Biological Chemistry. 2011 ; Vol. 392, No. 4. pp. 347-356.
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Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site. / Ahn, Jin Hyung; Lee, Ho Jeong; Lee, Eun Kyoung; Yu, Hyun Kyung; Lee, Tae Ho; Yoon, Yeup; Kim, Sun Jin; Kim, Jang Seong.

In: Biological Chemistry, Vol. 392, No. 4, 01.04.2011, p. 347-356.

Research output: Contribution to journalArticle

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