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1.
J Biochem ; 172(3): 165-175, 2022 Sep 05.
Article in English | MEDLINE | ID: mdl-35687058

ABSTRACT

Non-triple helical collagen polypeptide α1(IV) (NTH α1(IV)) is a gene product of COL4A1 and is secreted as a polypeptide chain without the triple helix structure under physiological conditions. Studies have shown that NTH α1(IV) is up-regulated in and around vascular endothelial cells during neovascularization and vascular-like networks of in vitro angiogenesis models, suggesting its involvement in angiogenesis. In the present study, we examined the effect of NTH α1(IV) on endothelial cell-to-cell junctions, and we found that NTH α1(IV) suppressed VE-cadherin (vascular endothelial cadherin) mediated junctions and promoted cellular migration in human umbilical vein endothelial cell cultures. NTH α1(IV) is potentially a factor that induces VE-cadherin endocytosis and promotes neovascular sprouting and elongation. The possible mechanism entails endocytosis of NTH α1(IV) by its cellular receptor(s), Endo180 and/or other proteins, which results in the clearance of the cellular receptor(s) from the cell surface, thus inducing the endocytosis of VE-cadherin. Because the NC1 domain of the α1 chain of type IV collagen, called arresten, is considered an endogenous inhibitor of angiogenesis, it seems that the single polypeptide chain of NTH α1(IV) has conflicting functions.


Subject(s)
Cadherins , Collagen Type IV , Antigens, CD , Cadherins/metabolism , Collagen Type IV/chemistry , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Intercellular Junctions/metabolism , Neovascularization, Pathologic/metabolism , Peptides/metabolism
2.
J Biochem ; 168(4): 355-363, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-32343811

ABSTRACT

Plasmin (Pm) is a serine protease that can dissolve fibrin clots. Several possible functions of Pm in blood other than fibrinolysis have been proposed. To explore the effects of Pm on primary haemostasis, we evaluated the cleavage of von Willebrand factor multimers (VWFMs) in human plasma by streptokinase (SK)-activated plasminogen (Pg) and the binding ability of the digested VWFMs to collagen. SK-activated Pg and ADAMTS13 (a VWF-cleaving enzyme) in human plasma cleaved VWFMs in conformation-dependent manners through dialysis to the urea-containing buffer. However, VWFMs in human plasma under vortex-based shear stress were cleaved by SK-activated Pg but not by ADAMTS13. These results suggested that the VWFM-cleavage sites in human plasma are exposed to some extent by vortex-based shear stress for Pm but not for ADAMTS13. Additionally, we revealed that cleavage by SK-activated Pg reduced VWFMs' binding ability to collagen, and VWFMs in human plasma were cleaved by Pm at several sites. These results suggest that SK-activated Pg degrades VWFMs, reduces their binding abilities to collagen and affects primary haemostasis. Because excessive Pg activation can degrade fibrinogen/fibrin, we propose that SK-activated Pg in blood may cause impaired primary and secondary haemostasis.


Subject(s)
Collagen/blood , Plasminogen/metabolism , von Willebrand Factor/metabolism , ADAMTS13 Protein/metabolism , Hemostasis , Humans , Protein Multimerization , Structure-Activity Relationship , von Willebrand Factor/chemistry
3.
J Biochem ; 163(5): 381-389, 2018 May 01.
Article in English | MEDLINE | ID: mdl-29228282

ABSTRACT

Thrombotic thrombocytopenic purpura (TTP) is caused by inactivation of a von Willebrand factor (VWF)-cleaving enzyme, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which leads to platelet-rich thrombi comprising unusually large VWF multimers. We have found that ADAMTS13 can bind to the inactivated form of plasmin. In addition, plasmin cleaves purified ADAMTS13 into several fragments and inactivates it. Hence, we hypothesized that activation of plasminogen to plasmin becomes a new-onset factor for TTP due to ADAMTS13 inactivation. Plasmin was added exogenously or activated from plasminogen by streprokinase addition in human plasma (HP). ADAMTS13 digestion and effects of the digestion on ADAMTS13 activity were evaluated. Exogenous plasmin cleaved ADAMTS13 into several fragments, but a portion of ADAMTS13 remained in full-length form. Digestion profile of ADAMTS13 with streprokinase added exogenously in HP was similar to that of ADAMTS13 with exogenous plasmin. ADAMTS13 activity measured using FRETS-VWF73 decreased to ∼40% compared with that for normal plasma. Endogenous VWF multimer-cleaving activity was attenuated more severely (∼10%). These data suggest that endogenous plasmin cleaves ADAMTS13 into fragments and reduces its activity to ∼10%. We suggest that endogenous plasmin activation alone is not sufficient to cause TTP, but plasmin activation with ADAMTS13 deficiency might increase the risk of TTP onset.


Subject(s)
ADAMTS13 Protein/metabolism , Fibrinolysin/metabolism , Proteolysis , Purpura, Thrombotic Thrombocytopenic/metabolism , ADAMTS13 Protein/blood , Humans , Risk Factors , von Willebrand Factor/metabolism
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