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Semin Thromb Hemost 2007; 33(1): 041-045
DOI: 10.1055/s-2006-958460
Copyright © 2007 by Thieme Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Role of Protein C Inhibitor in Human Reproduction

Francisco España1 , Silvia Navarro1 , Pilar Medina1 , Esther Zorio1 , Amparo Estellés1
  • 1Hospital Universitario La Fe, Centro de Investigación, Valencia, Spain
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Publikationsverlauf

Publikationsdatum:
23. Januar 2007 (online)

    Lizenzen und Reprints

ABSTRACT

Protein C inhibitor (PCI) is a heparin-dependent serine protease inhibitor found in human plasma, urine, and other body fluids. In blood plasma, PCI is present at ~0.08 μM and inactivates activated protein C and other coagulation and fibrinolytic enzymes. In seminal plasma, PCI is present at 2.2 to 3.7 μM. The main sources of seminal PCI are the seminal vesicles, where it remains fully active. Following ejaculation, PCI completely looses its activity in approximately 2 hours, when it partially complexes with prostate-specific antigen, two plasminogen activators (urokinase-type and tissue-type plasminogen activators), and tissue kallikrein. PCI is also present in an active form in follicular fluid at ~0.1 μM. Purified functionally active human blood plasma-derived as well as inactive semen-derived PCI inhibited both binding and penetration of zona-free hamster oocytes by human sperm. The binding inhibition by PCI was dose dependent. A concentration of 0.04 μM PCI (~100-fold lower than that present in seminal plasma) inhibited 50% of the binding and penetration ability. Given that capacitated sperm used for in vitro fertilization usually contains more than 0.05 μM of PCI, fertilization rates might be significantly reduced. All of these data suggest that PCI is involved in human reproduction at several steps, including the fertilization process.

KEYWORDS

Protein C inhibitor - fertilization - sperm - seminal plasma - plasminogen activators

REFERENCES

  • 1 España F, Medina P, Navarro S, Zorio E, Estellés A, Aznar J. The multifunctional protein C system.  Curr Med Chem Cardiovasc Hematol Agents. 2005;  3 119-131
    CrossrefPubMedGoogle Scholar
  • 2 Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor: purification from human plasma and characterization.  J Biol Chem. 1983;  258 163-168
    PubMedGoogle Scholar
  • 3 España F, Berrettini M, Griffin J H. Purification and characterization of plasma protein C inhibitor.  Thromb Res. 1989;  55 369-384
    CrossrefPubMedGoogle Scholar
  • 4 Heeb M J, Griffin J H. Physiologic inhibition of human activated protein C by alpha 1-antitrypsin.  J Biol Chem. 1988;  263 11613-11616
    PubMedGoogle Scholar
  • 5 Heeb M J, Espana F, Griffin J H. Inhibition and complexation of activated protein C by two major inhibitors in plasma.  Blood. 1989;  73 446-454
    PubMedGoogle Scholar
  • 6 Heeb M J, España F, Geiger M, Collen D, Stump D, Griffin J H. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3.  J Biol Chem. 1987;  262 15813-15816
    PubMedGoogle Scholar
  • 7 Suzuki K, Nishioka J, Kusumoto H, Hashimoto S. Mechanism of inhibition of activated protein C by protein C inhibitor.  J Biochem Tokyo. 1984;  95 187-195
    PubMedGoogle Scholar
  • 8 España F, Griffin J H. Determination of functional and antigen protein C inhibitor and its complexes with activated protein C in plasma by ELISAs.  Thromb Res. 1989;  55 671-682
    CrossrefPubMedGoogle Scholar
  • 9 España F, Vicente V, Tabernero D, Scharrer I, Griffin J H. Determination of plasma protein C inhibitor and of two activated protein C-inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease.  Thromb Res. 1990;  59 593-608
    CrossrefPubMedGoogle Scholar
  • 10 Tabernero D, España F, Vicente V, Estellés A, Gilabert J, Aznar J. Protein C inhibitor and other components of the protein C pathway in patients with acute deep vein thrombosis during heparin treatment.  Thromb Haemost. 1990;  63 380-382
    PubMedGoogle Scholar
  • 11 Geiger M, Huber K, Wojta J et al.. Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo.  Blood. 1989;  74 722-728
    PubMedGoogle Scholar
  • 12 España F, Gruber A, Heeb M J, Hanson S R, Harker L A, Griffin J H. In vivo and in vitro complexes of activated protein C with two inhibitors in baboon.  Blood. 1991;  77 1754-1760
    PubMedGoogle Scholar
  • 13 España F, Estellés A, Fernández P J, Gilabert J, Sánchez-Cuenca J, Griffin J H. Evidence for the regulation of urokinase and tissue type plasminogen activators by the serpin, protein C inhibitor, in semen, and blood plasma.  Thromb Haemost. 1993;  70 989-994
    PubMedGoogle Scholar
  • 14 España F, Vicente V, Estellés A et al.. Activation of protein C and complex formation between protein C inhibitor and tissue plasminogen activator during thrombolytic therapy.  Fibrinolysis. 1993;  7 308-315
    CrossrefPubMedGoogle Scholar
  • 15 Vicente V, España F, Tabernero D, Aznar J, Estellés A, Griffin J H. Evidence of activation of the protein C pathway during acute vascular damage induced by Mediterranean spotted fever.  Blood. 1991;  78 416-422
    PubMedGoogle Scholar
  • 16 Fernández J A, España F, Gilabert J, Estellés A, Aznar J. Decreased levels of protein C inhibitor during pregnancy and puerperium.  Rev Iberoamer Tromb Hemostas. 1991;  4 189-192
    PubMedGoogle Scholar
  • 17 Alcaraz A, España F, Sánchez-Cuenca J et al.. Activation of the protein C pathway in acute sepsis.  Thromb Res. 1995;  79 83-93
    CrossrefPubMedGoogle Scholar
  • 18 Geiger M, Priglinger U, Griffin J H, Binder B R. Urinary protein C inhibitor.  J Biol Chem. 1991;  266 11851-11857
    PubMedGoogle Scholar
  • 19 España F, Fink E, Sánchez-Cuenca J, Gilabert J, Estellés A, Witzgall K. Complexes of tissue kallikrein with protein C inhibitor in human semen and urine.  Eur J Biochem. 1995;  234 641-649
    CrossrefPubMedGoogle Scholar
  • 20 Hayashi T, Nishioka J, Kamada H et al.. Characterization of a novel human protein C inhibitor (PCI) gene transgenic mouse useful for studying the role of PCI in physiological and pathological conditions.  J Thromb Haemost. 2004;  2 949-961
    CrossrefPubMedGoogle Scholar
  • 21 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
    CrossrefPubMedGoogle Scholar
  • 22 España F, Estellés A, Griffin J H, Aznar J. Interaction of plasma kallikrein with protein C inhibitor in purified mixtures and in plasma.  Thromb Haemost. 1991;  65 46-51
    PubMedGoogle Scholar
  • 23 España F, Snchez-Cuenca J, Vera C D, Estellés A, Gilabert J, Aznar J. A quantitative ELISA for the measurement of complexes of prostate-specific antigen with protein C inhibitor when using a purified standard.  J Lab Clin Med. 1993;  122 711-719
    PubMedGoogle Scholar
  • 24 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
    CrossrefPubMedGoogle Scholar
  • 25 Hong C Y, Chiang B N, Huang J J, Wu P. Two plasminogen activators, streptokinase and urokinase, stimulate human sperm motility.  Andrologia. 1985;  17 317-322
    PubMedGoogle Scholar
  • 26 Schill W B. Caffeine and kallikrein-induced stimulation of human sperm motility: a comparative study.  Andrologia. 1975;  7 229-236
    PubMedGoogle Scholar
  • 27 Laurell M, Christensson A, Abrahamsson P A, 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
    PubMedGoogle Scholar
  • 28 Odet F, Guyot R, Leduque P, Le Magueresse-Battistoni B. Evidence for similar expression of protein C inhibitor and the urokinase-type plasminogen activator system during mouse testis development.  Endocrinology. 2004;  145 1481-1489
    PubMedGoogle Scholar
  • 29 Deperthes D, Chapdelaine P, Tremblay R R et al.. Isolation of prostatic kallikrein hK2, also known as hGK-1, in human seminal plasma.  Biochim Biophys Acta. 1995;  1245 311-316
    PubMedGoogle Scholar
  • 30 Kise H, Nishioka J, Kawamura J, Suzuki K. Characterization of semenogelin II and its molecular interaction with prostate-specific antigen and protein C inhibitor.  Eur J Biochem. 1996;  238 88-96
    CrossrefPubMedGoogle Scholar
  • 31 Zheng X, Geiger M, Ecke S et al.. Inhibition of acrosin by protein C inhibitor and localization of protein C inhibitor to spermatozoa.  Am J Physiol. 1994;  267 C466-C472
    PubMedGoogle Scholar
  • 32 Moore A, Penfold L M, Johnson J L, Latchman D S, Moore H D. Human sperm-egg binding is inhibited by peptides corresponding to core region of an acrosomal serine protease inhibitor.  Mol Reprod Dev. 1993;  34 280-291
    CrossrefPubMedGoogle Scholar
  • 33 Elisen M G, van Kooij R J, Nolte M A et al.. Protein C inhibitor may modulate human sperm-oocyte interactions.  Biol Reprod. 1998;  58 670-677
    CrossrefPubMedGoogle Scholar
  • 34 Lwaleed B A, Greenfield R, Stewart A, Birch B, Cooper A J. Seminal clotting and fibrinolytic balance: a possible physiological role in the male reproductive system.  Thromb Haemost. 2004;  92 752-766
    PubMedGoogle Scholar
  • 35 España F, Sánchez-Cuenca J, Fernández P J et al.. Inhibition of human sperm-zona-free hamster oocyte binding and penetration by protein C inhibitor.  Andrologia. 1999;  31 217-223
    CrossrefPubMedGoogle Scholar
  • 36 He S, Lin Y L, Liu Y X. Functionally inactive protein C inhibitor in seminal plasma may be associated with infertility.  Mol Hum Reprod. 1999;  5 513-519
    CrossrefPubMedGoogle Scholar
  • 37 Uhrin P, Dewerchin M, Hilpert M et al.. Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility.  J Clin Invest. 2000;  106 1531-1539
    CrossrefPubMedGoogle Scholar
  • 38 Gianotten J, Schimmel A W, Van der Veen F, Lombardi M P, Meijers J C. Absence of mutations in the PCI gene in subfertile men.  Mol Hum Reprod. 2004;  10 807-813
    CrossrefPubMedGoogle Scholar

Francisco EspañaPh.D. 

Hospital Universitario La Fe Centro de Investigación, Av. Campanar

21 46009 Valencia, Spain

eMail: espanya_fra@gva.es

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