Antiangiogenic Function of Antithrombin is Dependent on its Conformational Variation: Implication for Other Serpins

Abstract

Endogenous angiogenesis inhibitor that specifically decreases tumor cell proliferation can be used to treat cancer since angiogenesis is required at every step of tumor progression and metastasis. Endothelial cells are the main target for the antiangiogenic therapy because they are non-transformed and easily accessible to angiogenic inhibitors. Antithrombin functions as a principal plasma protein inhibitor of blood coagulation proteinases and belongs to the family of serine protease inhibitors (serpins) which have common mechanism of inhibition. Antithrombin acquires a potent antiangiogenic activity upon conversion of the native molecule to cleaved or latent conformation. Cleaved and latent preparations of bovine and human plasma derived antithrombin inhibits capillary endothelial cell proliferation and the growth of human SK-NAS neuroblastoma and Lewis lung carcinoma tumors in mice but not the native antithrombin's. The native form of antithrombin binds with high affinity to vascular heparan sulfate proteoglycans containing a specific pentasaccharide sequence and it is this cofactor interaction that activates antithrombin to maximal rate of thrombin inhibition. Upon inhibitory complex formation with target proteinases the antithrombin undergoes stressed to relaxed transformation and lose their high affinity for pentasacchride. Low affinity relaxed conformation with reduced heparin binding like cleaved and latent are antiangiogenic but native high affinity heparin binding stressed conformation is not, indicating the critical importance of heparin affinity in antithrombin antiangiogenic function. Based on evidence of interactions of the endothelial cell growth factors bFGF (basic fibroblast growth factor) and VEGF (vascular endothelial cell growth factor) with heparin like molecule in matrix, the possibility of antiangiogenic antithrombin to interfere with endothelial cell growth and angiogenesis through heparin mediated mechanism deserves serious consideration and investigation. It is also possible that cleaved and latent conformations with reduced affinity for heparins can also induce conformational change in the antithrombin which can open an epitope on the antithrombin surface for appropriate interactions on the endothelial surface for better antiangiogenic activity. This review illustrates the potential of antithrombin and other serpin family members as endogenous antiangiogenic proteins.

Diagnostic and Prognostic Value of TAT, PIC, TM, and t-PAIC in Malignant Tumor Patients With Venous Thrombosis

“…TAT is a sensitive marker of thrombin production and an indicator of activation of the coagulation system. 18 – 20 Its formation is the best time to judge the anticoagulant treatment, and it can rise in the prethrombotic state. Thus, evaluation of TAT levels is suitable for the early diagnosis of thrombotic diseases and for monitoring thrombolytic therapy.…”

The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms

“…TAT depends on ATIII, and indicates the activation of the coagulation system [ 43 ]. Binding of TM with thrombin can reduce the activity of thrombin and enhance the activity of protein C [ 44 ].…”

Protein disulfide isomerase uses thrombin–antithrombin complex as a template to bind its target protein and alter the blood coagulation rates

“…Therefore, it is critical to decipher the mechanisms and pathways that influence the coagulation cascade indirectly and have the potential to modulate thrombosis. PDI is predominantly prothrombotic and ATIII is a central component of anticoagulation control through its inhibition of the (factor Xa) FXa, thrombin, (factor XIa) FXIa, and (factor IXa) FIXa [ 26 , 27 ]. Therefore, the influence of PDI on ATIII may provide clues to its regulation during inflammatory, stress, or hypoxic conditions, and the situations that are conducive to its release in plasma [ 28 ].…”