Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site
| Autor: | Jang Seong Kim, Hyun Kyung Yu, Tae Ho Lee, Jin Hyung Ahn, Eun Kyoung Lee, Sun Jin Kim, Yeup Yoon, Ho Jeong Lee |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Apolipoprotein B
medicine.medical_treatment Molecular Sequence Data Clinical Biochemistry Lysine Angiogenesis Inhibitors Fibrinogen Biochemistry Kringle domain Kringles In vivo Fibrinolysis medicine Humans Amino Acid Sequence Binding site Angiostatins Molecular Biology Apolipoproteins A Fibrin Binding Sites Angiostatin Dose-Response Relationship Drug biology Chemistry Thrombin Plasminogen Peptide Fragments Tissue Plasminogen Activator biology.protein medicine.drug |
| Zdroj: | Biological Chemistry. 392 |
| ISSN: | 1437-4315 1431-6730 |
| Popis: | 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 effectsin vivo. To address this issue, we investigated the effects of several antiangiogenic kringle proteins including angiostatin, apolipoprotein(a) kringles IV9-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 processin vitroand 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 lysine-binding antiangiogenic kringles. However, the clinical signi-ficance of these findings will require further validationin vivo. |
| Databáze: | OpenAIRE |
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