Oxidized antithrombin is a dual inhibitor of coagulation and angiogenesis: Importance of low heparin affinity
| Autor: | Akila Swaminathan, Mohammad Sazzad Khan, Asma Naseem, Mohamad Aman Jairajpuri, Asim Azhar, Suvro Chatterjee |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Proteases Protein Conformation Angiogenesis Neovascularization Physiologic Angiogenesis Inhibitors Serpin Biochemistry Antithrombins 03 medical and health sciences Structural Biology medicine Animals Humans Blood Coagulation Molecular Biology Reactive center Wound Healing Heparin Chemistry Antithrombin Endothelial Cells General Medicine Endothelial stem cell Chorioallantoic membrane 030104 developmental biology Factor Xa Immunology Biophysics Protein Multimerization Oxidation-Reduction Protein Binding medicine.drug |
| Zdroj: | International Journal of Biological Macromolecules. 82:541-550 |
| ISSN: | 0141-8130 |
| Popis: | Endogenous proteins that promote vascular endothelial cell based inhibition of angiogenesis are an attractive option for antitumor therapy. Inactive cleaved and latent conformations of antithrombin (AT) are antiangiogenic, but not its native form which is an inhibitor of proteases involved in blood coagulation. Unlike native, the cleaved and latent conformations are reactive center loop inserted conformations which binds heparin with very low affinity. We use a sulfoxy modified AT to assess the role of reactive center loop insertion and heparin affinity in antiangiogenic function. Chorioallantoic membrane assay (CAM) shows that antiangiogenic activity of latent and oxidized AT are better than thalidomide, a potent antiangiogenic drug. Wound healing experiments suggest that latent and oxidized conformations can influence endothelial cell migration. Latent and cleaved conformations of AT shows an increase in α-helical content in the presence of unfractionated heparin, but not the oxidized AT. Unlike the loop inserted polymer, cleaved and latent conformations, oxidized AT has factor Xa inhibitory activity indicating that loop insertion is not necessary for antiangiogenic role. The results of our study establish that active conformation of AT can become antiangiogenic while maintaining its anticoagulant activity possibly through chelation of low affinity heparin in the vicinity of endothelial cell. |
| Databáze: | OpenAIRE |
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