Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies

Version 1 : Received: 31 October 2020 / Approved: 2 November 2020 / Online: 2 November 2020 (09:53:03 CET)

How to cite: Capozzi, A.; Riitano, G.; Recalchi, S.; Manganelli, V.; Costi, R.; Saccoliti, F.; Pulcinelli, F.; Garofalo, T.; Misasi, R.; Longo, A.; Di Santo, R.; Sorice, M. Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies. Preprints 2020, 2020110008 (doi: 10.20944/preprints202011.0008.v1). Capozzi, A.; Riitano, G.; Recalchi, S.; Manganelli, V.; Costi, R.; Saccoliti, F.; Pulcinelli, F.; Garofalo, T.; Misasi, R.; Longo, A.; Di Santo, R.; Sorice, M. Effect of Heparanase Inhibitor on Tissue Factor Overexpression in Platelets and Endothelial Cells Induced by Anti-β2-GPI Antibodies. Preprints 2020, 2020110008 (doi: 10.20944/preprints202011.0008.v1).

Abstract

Anti-phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity associated with the presence of “anti-phospholipid antibodies”. Thrombosis may be the result of a hypercoagulable state related to activation of endothelial cells and platelets by anti-2-glycoprotein I (β2-GPI) antibodies. Anti-β2-GPI antibodies induce a proinflammatory and procoagulant phenotype in these cells that, after activation, express Tissue Factor (TF), the major initiator of the clotting cascade, playing a role in thrombotic manifestations. Moreover, TF expression may also be induced by Heparanase, an endo--D-glucuronidase, that generates heparan sulfate fragments, regulating inflammatory responses. In this study we analyzed, in human platelets and endothelial cells, the effect of a new symmetrical 2-aminophenyl-benzazolyl-5-acetate derivative (RDS3337), able to inhibit Heparanase activity, on signal transduction pathway leading to TF expression triggered by anti-β2-GPI. Platelets and endothelial cells were incubated with affinity purified anti-β2-GPI after pretreatment with RDS3337. Cell lysates were analyzed for phospho-interleukin-1 receptor-associated kinase 1 (IRAK1), phospho-p65 nuclear factor kappa B (NF-κB) and TF by Western blot. IRAK phosphorylation and consequent NF-κB activation, as well as TF expression, triggered by anti-β2-GPI treatment were significantly prevented by previous pretreatment with RDS3337. In the same vein, pretreatment with RDS3337 prevented platelet aggregation and ATP release triggered by anti-β2-GPI antibodies. These findings support the view of Heparanase involvement in a prothrombotic state related to APS syndrome, suggesting a novel target to regulate overexpression of procoagulant protein(s).

Subject Areas

platelets; endothelial cells; anti-phospholipid syndrome; anti-β2GPI; Tissue Factor; Heparanase inhibitor

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.