Download PDF
Thromb Haemost 2001; 86(06): 1521-1527
DOI: 10.1055/s-0037-1616757
Review Article
Schattauer GmbH

A Novel Function of Extraerythrocytic Hemoglobin

Identification of Globin as a Stimulant of Plasminogen Activator Biosynthesis in Human Fibroblasts
Etsuo Yoshida
Department of Physiology, Miyazaki Medical College, Miyazaki, Japan
,
Sayuri Ohmura
Department of Physiology, Miyazaki Medical College, Miyazaki, Japan
,
Masahiko Sugiki
Department of Physiology, Miyazaki Medical College, Miyazaki, Japan
,
Keita Anai
Department of Physiology, Miyazaki Medical College, Miyazaki, Japan
,
Masugi Maruyama
Department of Physiology, Miyazaki Medical College, Miyazaki, Japan
› Author Affiliations
Further Information

Publication History

Received 01 February 1999

Accepted after resubmission 08 August 2001

Publication Date:
12 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Following wounding, the surrounding fibroblasts migrate towards the clotted blood in the wounded space to form granulation tissue resulting in wound repair. One of the most abundant proteins in the wound is hemoglobin (Hb). The aim of the present study was to examine the effect of Hb on fibroblasts in producing components of the plasminogen-plasmin system which play an important role in wound healing. Human Hb Ao added to cultures of human fibroblasts elicited a dose-dependent increase in fibrinolytic activity. ELISA demonstrated an increased fibrinolytic activity due to increased urokinase-type plasminogen activator (uPA). An increase in tissue-type PA was also detected, while the type-1 PA inhibitor level remained unaffected. Globin showed a similar effect, while hemin and protoporphyrin IX exerted no effect. The influence of Hb was quenched when haptoglobin was added. Although northern blot analysis revealed no difference in uPA transcripts between stimulated and non-stimulated cells, immunopretipitation experiments confirmed an increased uPA synthesis in Hb- and globin-treated cells, suggesting that enhanced expression is achieved through translational regulation. These findings suggest a potential role for globin in modulating cellular functions during the process of wound healing.

Keywords

Hemoglobin - globin - wound healing - the plasminogen-plasmin system - fibrinolytic system - plasminogen activator
 

  • References

  • 1 Kwaan HC. The biologic role of components of the plasminogen-plasmin system. Prog Cardiovas Dis 1992; 34: 309-16.
    CrossrefPubMedGoogle Scholar
  • 2 Danø K, Rømer J, Nielsen BS, Bjorn S, Pyke C, Rygaard J, Lund LR. Cancer invasion and tissue remodeling-cooperation of prtease systems and cell types. APMIS 1999; 107: 120-7.
    CrossrefPubMedGoogle Scholar
  • 3 Kirchheimer JC, Wojita J, Christ G, Binder BR. Proliferation of a human epidermal tumor cell line stimulated by urokinase. FASEB J 1987; 1: 125-8.
    CrossrefPubMedGoogle Scholar
  • 4 Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999; 82: 259-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Del Rosso M, Fibbi G, Matucci Cernic M. The urokinase-type plasminogen activator system and inflammatory joint diseases. Clin Exp Rheumatol 1999; 17: 485-98.
    PubMedGoogle Scholar
  • 6 Blasi F. Proteolysis, cell adhesion, chemotaxis and invasiveness are regulated by the uPA-uPAR-PAI-1 system. Thromb Haemost 1999; 82: 298-304.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumor growth, invasion and metastasis. Cell Mol Life Sci 2000; 57: 25-40.
    CrossrefPubMedGoogle Scholar
  • 8 Grøndahl-Hansen J, Lund LR, Ralfkiaer E, Ottevanger V, Danø K. Urokinase- and tissue-type plasminogen activators in keratinocytes during wound reepithelialization in vivo. J Invest Dermatol 1988; 90: 790-5.
    CrossrefPubMedGoogle Scholar
  • 9 Rømer J, Lund LR, Eriksen J, Ralfkiaer E, Zeheb R, Gelehrter TD, Danø K. Differential expression of urokinase-type plasminogen activator and its type-1 inhibitor during healing of mouse skin wounds. J Invest Dermatol 1991; 97: 803-11.
    CrossrefPubMedGoogle Scholar
  • 10 Schefer BM, Maier K, Eickhoff U, Todd RF, Kramer MD. Plasminogen activation in healing human wounds. Am J Pathol 1994; 144: 1269-80.
    PubMedGoogle Scholar
  • 11 Pawar S, Kartha S, Toback FG. Differential gene expression in migrating renal epithelial cells after wounding. J Cell Physiol 1995; 165: 556-65.
    CrossrefPubMedGoogle Scholar
  • 12 Carmeliet P, Schoonjans L, Kieckens L, Ream B, Degen J, Bronson R, DeVos R, van den Oord JJ, Collen D, Mulligan R. Physiological consequences of loss of plasminogen activator gene function in mice. Nature 1994; 368: 419-24.
    CrossrefPubMedGoogle Scholar
  • 13 Rømer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Danø K. Impaired wound haling in mice with a disrupted plasminogen gene. Nat Med 1996; 2: 287-92.
    CrossrefPubMedGoogle Scholar
  • 14 Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F, Collen D, Gerard RD. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation 1997; 96: 3180-91.
    CrossrefPubMedGoogle Scholar
  • 15 Carmeliet P, Moons L, Dewerchin M, Rosenberg S, Herbert JM, Lupu F, Collen D. Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice. J Cell Biol 1998; 140: 233-45.
    CrossrefPubMedGoogle Scholar
  • 16 Creemers E, Cleutjens J, Smits J, Heymans S, Moons L, Collen D, Daemen M, Carmeliet P. Disruption of the plasminogen gene in mice abolishes wound healing after myocardial infarction. Am J Pathol 2000; 156: 1865-73.
    CrossrefPubMedGoogle Scholar
  • 17 Huisman THJ. Separation of hemoglobins and hemoglobin chains by high-performance liquid chromatography. J Chromatogr 1987; 418: 277-304.
    CrossrefPubMedGoogle Scholar
  • 18 Yoshida E, Verrusio EN, Mihara H, Oh DY, Kwaan HC. Enhancement of the expression of urokinase-type plasminogen activator from PC-3 human prostate cancer cells by thrombin. Cancer Res 1994; 54: 3300-4.
    PubMedGoogle Scholar
  • 19 Everse J, Johnson MC, Marini MA. Peroxidative activities of hemoglobin and hemoglobin derivatives. Method Enzymol 1994; 231: 547-61.
    PubMedGoogle Scholar
  • 20 Zilletti L, Ciuffi M, Franchi-Micheli S, Fusi F, Gentilini G, Moneti G, Valoti M, Sgaragli GP. Cyclooxygenase activity of hemoglobin. Method Enzymol 1994; 231: 562-72.
    PubMedGoogle Scholar
  • 21 Everse J, Hsia N. The toxicities of native and modified hemoglobins. Free Radic Biol Med 1997; 22: 1075-99.
    CrossrefPubMedGoogle Scholar
  • 22 Elkins C. Identification and purification of a conserved heme-regulated hemoglobin-binding outer membrane protein from Haemophilus ducreyi. Infect Immun 1995; 63: 1241-5.
    PubMedGoogle Scholar
  • 23 Lewis LA, Dyer DW. Identification of an iron-regulated outer membrane protein of Neisseria meningitidis involved in the utilization of hemoglobin complexed to haptoglobin. J Bacteriol 1995; 177: 1299-306.
    CrossrefPubMedGoogle Scholar
  • 24 Chen C, Sparling F, Lewis LW, Dyer DW, Elkins C. Identification and purification of a hemoglobin-binding outer membrane protein from Neisseria gonorrhoeae. Infect Immunol 1996; 64: 5008-14.
    PubMedGoogle Scholar
  • 25 Schally AV, Baba Y, Nair RMG. The amino acid sequence of a peptide with growth hormone-releasing activity isolated from porcine hypothalamus. J Biol Chem 1971; 246: 6647-50.
    PubMedGoogle Scholar
  • 26 Ivanov VT, Karelin AA, Philoppova MM, Nazimov IV, Pletnev VZ. Hemoglobin as a source of endogenous bioactive peptides: The concept of tissue-specific peptide pool. Biopoly 1997; 43: 171-88.
    CrossrefPubMedGoogle Scholar
  • 27 Galoyan AA. Primary structure and biological activity of hemoglobin-related hypothalamic peptides. Biopoly 1975; 43: 135-7.
    PubMedGoogle Scholar