Novel peptides that inhibit heparanase activation of the coagulation system.

Abstract

Heparanase is implicated in cell invasion, tumour metastasis and angiogenesis. It forms a complex and enhances the activity of the blood coagulation initiator - tissue factor (TF). We describe new peptides derived from the solvent accessible surface of TF pathway inhibitor 2 (TFPI-2) that inhibit the heparanase procoagulant activity. Peptides were evaluated in vitro by measuring activated coagulation factor X levels and co-immunoprecipitation. Heparanase protein and/or lipopolysaccharide (LPS) were injected intra-peritoneally and inhibitory peptides were injected subcutaneously in mouse models. Plasma was analysed by ELISA for thrombin-antithrombin complex (TAT), D-dimer as markers of coagulation activation, and interleukin 6 as marker of sepsis severity. Peptides 5, 6, 7, 21 and 22, at the length of 11-14 amino acids, inhibited heparanase procoagulant activity but did not affect TF activity. Injection of newly identified peptides 5, 6 and 7 significantly decreased or abolished TAT plasma levels when heparanase or LPS were pre-injected, and inhibited clot formation in an inferior vena cava thrombosis model. To conclude, the solvent accessible surface of TFPI-2 first Kunitz domain is involved in TF/heparanase complex inhibition. The newly identified peptides potentially attenuate activation of the coagulation system induced by heparanase or LPS without predisposing to significant bleeding tendency.

• Authors: E Axelman, I Henig, Y Crispel, J Attias, J-P Li, B Brenner, I Vlodavsky, Y Nadir
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 112 Issue 3 Pg. 466-77 (Sep 02 2014) ISSN: 2567-689X [Electronic] Germany
• PMID: 25030319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrin Fibrinogen Degradation Products
• Glycoproteins
• Interleukin-6
• Lipopolysaccharides
• Peptide Fragments
• fibrin fragment D
• tissue-factor-pathway inhibitor 2
• Factor X
• Thromboplastin
• heparanase
• Glucuronidase
• Thrombin

Topics

• Animals
• Blood Coagulation (drug effects)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Factor X (metabolism)
• Fibrin Fibrinogen Degradation Products (metabolism)
• Glucuronidase (antagonists & inhibitors, genetics)
• Glycoproteins (administration & dosage)
• HEK293 Cells
• Humans
• Interleukin-6 (metabolism)
• Lipopolysaccharides (immunology)
• Mice
• Mice, Inbred ICR
• Mice, Knockout
• Peptide Fragments (administration & dosage)
• Thrombin (metabolism)
• Thromboplastin (metabolism)
• Thrombosis (blood, drug therapy)
• Vena Cava, Inferior (metabolism)