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Biochemistry (Moscow)

, Volume 74, Issue 10, pp 1104–1113 | Cite as

Inhibitory effect of angiostatins on activity of the plasminogen/plasminogen activator system

  • R. B. AisinaEmail author
  • L. I. Mukhametova
  • D. A. Gulin
  • M. Y. Levashov
  • N. V. Prisyazhnaya
  • K. B. Gershkovich
  • S. D. Varfolomeyev
Article

Abstract

Angiostatins, kringle-containing fragments of plasminogen, are potent inhibitors of angiogenesis. Effects of three angiostatin forms, K1–3, K1–4, and K1-4.5 (0–2 µM), on the rate of native Glu-plasminogen activation by its physiological activators in the absence or presence of soluble fibrin were investigated in vitro. Angiostatins did not affect the intrinsic amidolytic activities of plasmin and plasminogen activators of tissue type (tPA) and urokinase type (single-chain scuPA and two-chain tcuPA), but inhibited conversion of plasminogen to plasmin in a dose-dependent manner. All three angiostatins suppressed Glu-plasminogen activation by tcuPA independently of the presence of fibrin, and the inhibitory effect increased in the order: K1-3 < K1-4 < K1-4.5. The inhibitory effects of angiostatins on the scuPA activator activity were lower and further decreased in the presence of fibrin. Angiostatin K1-3 (up to 2 µM) had no effect, while 2 µM angiostatins K1-4 and K1-4.5 inhibited the fibrin-stimulated Glu-plasminogen activation by tPA by 50 and 100%, respectively. The difference in effects of the three angiostatins on the Glu-plasminogen activation by scuPA, tcuPA, and tPA in the absence or presence of fibrin is due to the differences in angiostatin structures, mechanisms of action, and fibrin-specificity of plasminogen activators, as well as due to the influence of fibrin on the Glu-plasminogen conformation. Angiostatins in vivo, which mimic plasminogen-binding activity, can inhibit plasminogen activation stimulated by various proteins (including fibrin) of extracellular matrix, thereby blocking cell migration and angiogenesis. The data of this work indicate that the inhibition of Glu-plasminogen activation under the action of physiological plasminogen activators by angiostatins can be implicated in the complex mechanism of their antiangiogenic and antitumor action.

Key words

plasminogen plasminogen activator plasmin angiostatin inhibition of plasminogen activation 

Abbreviations

AFK-pNA

HCO-Ala-Phe-Lys p-nitroanilide

6-AHA

6-aminohexanoic acid

α2-AP

α2-antiplasmin

Glu-Pg and Lys-Pg

Glu- and Lys-form of plasminogen, respectively

LBS

lysine-binding center

MMPs

matrix metal proteinases

NTP

NH2-terminal peptide

PA(s)

plasminogen activator(s)

PAI-1

plasminogen activator inhibitor-1

Pm

plasmin

scuPA

single-chain urokinase-type plasminogen activator (pro-urokinase)

tcuPA

two-chain urokinase-type plasminogen activator (urokinase)

tPA

tissue-type plasminogen activator

SK

streptokinase

S-2444

Glp-Gly-Arg p-nitroanilide

S-2288

H,D-Ile-Pro-Arg p-nitroanilide

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Copyright information

© Pleiades Publishing, Ltd. 2009

Authors and Affiliations

  • R. B. Aisina
    • 1
    Email author
  • L. I. Mukhametova
    • 1
  • D. A. Gulin
    • 2
  • M. Y. Levashov
    • 1
  • N. V. Prisyazhnaya
    • 1
  • K. B. Gershkovich
    • 2
  • S. D. Varfolomeyev
    • 1
  1. 1.Faculty of ChemistryLomonosov Moscow State UniversityMoscowRussia
  2. 2.Emanuel Institute of Biochemical PhysicsRussian Academy of SciencesMoscowRussia

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