Abstract Number: PB0768
Meeting: ISTH 2021 Congress
Background: It is known that plasminogen heavy chain degradation products containing K1-3, K1-4 and K1-4.5 kringle domains, called angiostatins, inhibit angiogenesis and tumor growth. Angiostatin K1-4.5 is the most effective inhibitor of endothelial cell proliferation, neovascularization and tumor growth.
Aims: Comparison of inhibitory effect of K1-4.5 and a new K1-5 fragment containing intact kringle 5 on the Glu-plasminogen (Pg) activation by its activators and on corneal neovascularization.
Methods: Intact K1-5 and K1-4.5 were prepared from human plasminogen. Their influence on Pg activation kinetics by tPA (in presence of soluble fibrin) and uPA was measured by conjugated method.
Results: Fragments K1-4.5 and K1-5 did not affect the amidolytic activity of plasmin, tPA and uPA, but inhibited the Pg activation by uPA and tPA in dose-dependent manner. The kPg and KPg values of Pg activation in absence of the fragments were 0.02 s-1 and 0.52 μM for uPA and 0.086 s-1 and 0.023 μM for tPA, respectively. Both fragments had no effect on kPg and increased KPg of Pg activation by uPA, whereas they reduced kPg and increased KPg of Pg activation by tPA. Inhibition constants by K1-4.5 and K1-5 were 0.59 and 0.12 μM for uPA and 0.4 and 0.05 μM for tPA, respectively. Experiments on the use of these fragments in the treatment of rabbit eyes burn have shown that K1-5 suppresses corneal neovascularization more strongly than K1-4.5.
Conclusions: The K1-4.5 and K1-5 displace Pg from uPA-Pg and tPA-Pg complexes and from fibrin surface in case of tPA. Absence of protease domain in these fragments leads to decreasing the concentrations of uPA-Pg and tPA-Pg-fibrin activator complexes and consequently reducing the plasmin generation rate. Owing the kringle 5 integrity, K1-5 stronger inhibits Pg activation and angiogenesis, than K1-4.5. Intact K1-5 is promising for suppressing endothelial cells proliferation and neovascularization.
To cite this abstract in AMA style:Gershkovich K, Mukhametova L, Aisina R. The Intact Heavy Chain of Plasminogen Supresses Angiogenesis More Strongly than the Known Angiostatin [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/the-intact-heavy-chain-of-plasminogen-supresses-angiogenesis-more-strongly-than-the-known-angiostatin/. Accessed December 7, 2021.
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