OBJECTIVE: Regulation of the conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) is critical in the control of fibrin deposition. While several plasminogen activators have been described, soluble plasma cofactors that stimulate fibrinolysis have not been characterized. The purpose of this study was to investigate the effects of beta(2)-glycoprotein I (beta(2)GPI), an abundant plasma glycoprotein, on tPA-mediated plasminogen activation. METHODS: The effect of beta(2)GPI on tPA-mediated activation of plasminogen was assessed using amidolytic assays, a fibrin gel, and plasma clots. Binding of beta(2)GPI to tPA and plasminogen was determined in parallel. The effects of IgG fractions and anti-beta(2)GPI antibodies from patients with antiphospholipid syndrome (APS) on tPA-mediated plasminogen activation were also measured. RESULTS: Beta(2)-glycoprotein I stimulated tPA-dependent plasminogen activation in the fluid phase and within a fibrin gel. The beta(2)GPI region responsible for stimulating tPA activity was shown to be at least partly contained within beta(2)GPI domain V. In addition, beta(2)GPI bound tPA with high affinity (K(d) approximately 20 nM), stimulated tPA amidolytic activity, and caused an overall 20-fold increase in the catalytic efficiency (K(cat)/K(m)) of tPA-mediated conversion of Glu-plasminogen to plasmin. Moreover, depletion of beta(2)GPI from plasma led to diminished rates of clot lysis, with restoration of normal lysis rates following beta(2)GPI repletion. Stimulation of tPA-mediated plasminogen activity by beta(2)GPI was inhibited by monoclonal anti-beta(2)GPI antibodies as well as by anti-beta(2)GPI antibodies from patients with APS. CONCLUSION: These findings suggest that beta(2)GPI may be an endogenous regulator of fibrinolysis. Impairment of beta(2)GPI-stimulated fibrinolysis by anti-beta(2)GPI antibodies may contribute to the development of thrombosis in patients with APS.
OBJECTIVE: Regulation of the conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) is critical in the control of fibrin deposition. While several plasminogen activators have been described, soluble plasma cofactors that stimulate fibrinolysis have not been characterized. The purpose of this study was to investigate the effects of beta(2)-glycoprotein I (beta(2)GPI), an abundant plasma glycoprotein, on tPA-mediated plasminogen activation. METHODS: The effect of beta(2)GPI on tPA-mediated activation of plasminogen was assessed using amidolytic assays, a fibrin gel, and plasma clots. Binding of beta(2)GPI to tPA and plasminogen was determined in parallel. The effects of IgG fractions and anti-beta(2)GPI antibodies from patients with antiphospholipid syndrome (APS) on tPA-mediated plasminogen activation were also measured. RESULTS:Beta(2)-glycoprotein I stimulated tPA-dependent plasminogen activation in the fluid phase and within a fibrin gel. The beta(2)GPI region responsible for stimulating tPA activity was shown to be at least partly contained within beta(2)GPI domain V. In addition, beta(2)GPI bound tPA with high affinity (K(d) approximately 20 nM), stimulated tPA amidolytic activity, and caused an overall 20-fold increase in the catalytic efficiency (K(cat)/K(m)) of tPA-mediated conversion of Glu-plasminogen to plasmin. Moreover, depletion of beta(2)GPI from plasma led to diminished rates of clot lysis, with restoration of normal lysis rates following beta(2)GPI repletion. Stimulation of tPA-mediated plasminogen activity by beta(2)GPI was inhibited by monoclonal anti-beta(2)GPI antibodies as well as by anti-beta(2)GPI antibodies from patients with APS. CONCLUSION: These findings suggest that beta(2)GPI may be an endogenous regulator of fibrinolysis. Impairment of beta(2)GPI-stimulated fibrinolysis by anti-beta(2)GPI antibodies may contribute to the development of thrombosis in patients with APS.
Authors: Menno van Lummel; Maarten T T Pennings; Ronald H W M Derksen; Rolf T Urbanus; Bianca C H Lutters; Niels Kaldenhoven; Philip G de Groot Journal: J Biol Chem Date: 2005-08-09 Impact factor: 5.157
Authors: Y Sheng; S W Reddel; H Herzog; Y X Wang; T Brighton; M P France; S A Robertson; S A Krilis Journal: J Biol Chem Date: 2001-01-05 Impact factor: 5.157
Authors: Sherry D Fleming; Michael R Pope; Sara M Hoffman; Tiffany Moses; Urska Bukovnik; John M Tomich; Lynn M Wagner; Keith M Woods Journal: J Immunol Date: 2010-10-18 Impact factor: 5.422
Authors: Zurina Romay-Penabad; Maria Guadalupe Montiel-Manzano; Tuya Shilagard; Elizabeth Papalardo; Gracie Vargas; Arun B Deora; Michael Wang; Andrew T Jacovina; Ethel Garcia-Latorre; Elba Reyes-Maldonado; Katherine A Hajjar; Silvia S Pierangeli Journal: Blood Date: 2009-07-23 Impact factor: 22.113