Subscribe to RSS
DOI: 10.1055/s-0038-1649712
Evidence for the Regulation of Urokinase and Tissue Type Plasminogen Activators by the Serpin, Protein C Inhibitor, in Semen and Blood Plasma
Publication History
Received 03 March 1993
Accepted after revision 19 August 1993
Publication Date:
06 July 2018 (online)
Summary
Since the serine protease inhibitor, protein C inhibitor (PCI), is present in seminal plasma at ≈3 μM, complexes of PCI with urokinase (uPA) and tissue type (tPA) plasminogen activator were quantitated using sandwich enzyme-linked immunosorbent assays (ELISA’s). Seminal plasma (N = 10) collected in the absence of extrinsic inhibitors had a mean of 25 ± 5 ng/ml uPA: PCI, 76 ± 23 ng/ml tPA: PCI, and 4 ± 2 ng/ml of tPA complexes with plasminogen activator inhibitor-1 (tPA:PAI-l). 93% of the uPA and 17% of the tPA antigen in seminal plasma was in complex with PCI and, when complexation was inhibited by collecting semen into an 1,10-phenanthrolinium solution, 33% of the uPA and 7% of the tPA was complexed to PCI. Urine (N = 10) contained 4 ± 1 ng/ml uPA:PCI. In purified system, complexation of uPA and tPA to PCI paralleled the inhibition of the enzymes. In vitro studies in blood and seminal plasma showed that heparin stimulated complexation of uPA and tPA with PCI, suggesting that negatively charged glycosaminoglycans in blood vessels and in the reproductive system may regulate PCI reactions with uPA and tPA. These results suggest that PCI is a physiologic regulator of uPA and tPA in male reproductive tissues and raises questions about a potential role of PCI in human fertility and in uPA-dependent cell invasiveness.
-
References
- 1 Stenflo J. A new vitamin K-dependent protein: Purification from bovine plasma and preliminary characterization. J Biol Chem 1976; 251: 355-363
- 2 Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-5831
- 3 Marlar RA, Kleiss AJ, Griffin JH. Mechanism of activation of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067-1072
- 4 Sakata Y, Curriden S, Lawrence D, Griffin JH, Loskutoff DJ. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci USA 1985; 1121-1125
- 5 van HinsbergVWM, Bertina RM, van WijngaardenA, van TilburgNH, Emeis JJ, Haverkate F. Activated protein C decreases plasminogen activator-inhibitor activity in endothelial cell-conditioned medium. Blood 1985; 65: 444-451
- 6 Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor. Purification from human plasma and characterization. J Biol Chem 1983; 258: 163-168
- 7 España F, Berrettini M, Griffin JH. Purification and characterization of plasma protein C inhibitor. Thromb Res 1989; 55: 369-384
- 8 Meijers JCM, Kanters DHAJ, Vlooswijk RAA, Van ErpHE, Messing M, Bouma BN. Inactivation of human plasma kallikrein and factor XI a by protein C inhibitor. Biochemistry 1988; 27: 4231-4237
- 9 Laurell M, Stenflo J. Protein C inhibitor from human plasma: Characterization of native and cleaved inhibitor and demonstration of inhibitor complexes with plasma kallikrein. Thromb Haemostas 1989; 62: 885-891
- 10 Heeb MJ, España F, Geiger M, Collen D, Stump D, Griffin JH. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3. J Biol Chem 1987; 262: 15813-15816
- 11 Stief TW, Radke KP, Heimburger N. Evidence for identity of PCI and plasminogen activator inhibitor 3. Biol Chem Hoppe-Seyler 1987; 368: 1427-1433
- 12 España F. Complexes of activated protein C with its inhibitors. In: Protein C pathway. Aznar J, España F. (eds). Barcelona, Berlin: Springer; 1991: 61-75
- 13 España F, Gruber A, Heeb MJ, Hanson SR, Harker LA, Griffin JH. In vivo and in vitro complexes of activated protein C with two inhibitors in baboon. Blood 1991; 77: 1754-1760
- 14 Geiger M, Huber K, Wojta J, Stingl L, España F, Griffin JH, Binder BR. Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo. Blood 1989; 74: 722-728
- 15 España F, Vicente V, Vazquez L, Aznar J. Contribution of protein C inhibitor (plasminogen activator inhibitor-3) to the inhibition of tissue plasminogen activator during thrombolytic therapy. Blood 1991; 78: 494A (abstr)
- 16 Vicente V, España F, Tabernero D, Aznar J, Estellés A, Griffin JH. Evidence of activation of the protein C pathway during acute vascular damage induced by Mediterranean spotted fever. Blood 1991; 78: 416-422
- 17 España F, Gilabert J, Estellés A, Romeu A, Aznar J, Cabo A. Functionally active protein C inhibitor/plasminogen activator inhibitor-3 (PCI/PAI-3) is secreted in seminal vesicles, occurs at high concentrations in human seminal plasma and complexes with prostate-specific antigen. Thromb Res 1991; 64: 309-320
- 18 Laurell M, Christensson A, Abrahamsson PA, Stenflo J, Lilja H. Protein C inhibitor in human body fluids. Seminal plasma is rich in inhibitor antigen deriving from cells throughout the male reproductive system. J Clin Invest 1992; 89: 1094-1101
- 19 Ecke S, Geiger M, Resch I, Jerabek I, Stingl L, Maier M, Binder BR. Inhibition of tissue kallikrein by protein C inhibitor. Evidence for identity of protein C inhibitor with the kallikrein binding protein. J Biol Chem 1992; 267: 7048-7052
- 20 España F, Estellés A, Aznar J, Gilabert J. Assay of protein C in human plasma: Comparison of amidolytic, coagulation and immunochemical assays. Thromb Res 1986; 44: 771-782
- 21 España F, Griffin JH. Determination of functional and antigen protein C inhibitor and its complexes with activated protein C in plasma by ELISA’s. Thromb Res 1989; 55: 671-682
- 22 España F, Vicente V, Estellés A, Vazquez L, Hendl S, Sánchez-Cuencha J, Aznar J. Complex formation between protein C inhibitor and tissue plasminogen activator during thrombolytic therapy. Evidence of activation of protein C pathway. Fibrinolysis 1993; 7: 308-315
- 23 Astedt B, Wallen P, Aasted B. Occurrence of both urokinase and tissue plasminogen activator in human seminal plasma. Thromb Res 1979; 16: 463-472
- 24 Stump DC, Thienpont M, Collen D. Purification and characterization of a novel inhibitor of urokinase from human urine. J Biol Chem 1986; 261: 12759-12766
- 25 Smokovitis A, Nokolis N, Alexopoulos C, Alexaki E, Eleftheriou E. Plasminogen activator activity, plasminogen activator inhibition and plasmin inhibition in Spermatozoa and seminal plasma of man and various animal species. Effect of plasmin on sperm motility. Fibrinolysis 1987; 1: 253-257
- 26 Hong CY, Chiang BN, Huang JJ, Wu P. Two plasminogen activators, streptokinase and urokinase, stimulate human sperm motility. Andrologia 1985; 17: 317-322
- 27 Schill WB. Caffeine and kallikrein-induced stimulation of human sperm motility; A comparative study. Andrologia 1975; 7: 229-236
- 28 Izzo PL, Canale D, Bianchi B, Menchini P, Esposito G, Menchini-Fabris GF, Fasani R, Ohnmeiss H. The treatment of male subfertility with kallikrein. Andrologia 1984; 16: 156-161
- 29 Van DredenP, Gonzalés J, Poirot C. Human seminal fibrinolytic activity: specific determinations of tissue plasminogen activator and urokinase. Andrologia 1991; 23: 29-33
- 30 Saksela O, Rifkin DB. Cell-associated plasminogen activation: regulation and physiological functions. Annu Rev Cell Biol 1988; 4: 093-126
- 31 Janicke F, Schmitt M, Ulm K, Gossner W, Graeff H. The urokinase-type plasminogen activator (u-PA) antigen is related to early relapse in breast cancer. Lancet 1989; 2: 1049-1051
- 32 Murano G, Aronson D, Williams L, Brown L. The inhibition of high and low molecular weight urokinase in plasma. Blood 1980; 55: 430-436