Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site
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Jin-Hyung Ahn
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 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 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 lysine-binding antiangiogenic kringles. However, the clinical signi-ficance of these findings will require further validation in vivo.
©2011 by Walter de Gruyter Berlin New York
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Articles in the same Issue
- Guest Editorial
- Highlight: Mechanisms of RNA-mediated regulation
- HIGHLIGHT: 62ND MOSBACH COLLOQUIUM OF THE GBM ‘MECHANISMS OF RNA-MEDIATED REGULATION’
- Clustered regularly interspaced short palindromic repeats (CRISPRs): the hallmark of an ingenious antiviral defense mechanism in prokaryotes
- Regulatory RNAs in cyanobacteria: developmental decisions, stress responses and a plethora of chromosomally encoded cis-antisense RNAs
- RNA-dependent RNA polymerases in RNA silencing
- Traces of post-transcriptional RNA modifications in deep sequencing data
- Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs
- PROTEIN STRUCTURE AND FUNCTION
- The effects of a plant proteinase inhibitor from Enterolobium contortisiliquum on human tumor cell lines
- Role of unique basic residues in cytotoxic, antibacterial and antiparasitic activities of human eosinophil cationic protein
- Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site
- Changing nucleotide specificity of the DEAD-box helicase Hera abrogates communication between the Q-motif and the P-loop
- Identification of plasma haptoglobin forms which loosely bind hemoglobin
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- Organelle stress-induced activating transcription factor-3 downregulates low-density lipoprotein receptor expression in Sk-Hep1 human liver cells
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