Disease relevance of HRG

• To define the role of HRG, plasma titers were measured by single radial immunodiffusion in eleven patients with thromboembolism before and after streptokinase (SK) therapy and were found unchanged (84.7 +/- 6.2%, M +/- SEM before, and 99.5 +/- 6.3% after 12 hr of SK therapy) [1].
• In assays performed in vitro of endothelial cell migration and tube formation, and in vivo corneal angiogenesis assays, HRGP inhibited the antiangiogenic effect of TSP-1 [2].
• HRGP colocalized with TSP-1 in the stroma of human breast cancer specimens, and this interaction masked the antiangiogenic epitope of TSP-1 [2].
• High levels of histidine-rich glycoprotein (HRGP) and plasminogen activator inhibitor-1 (PAI-1) have been claimed to contribute to the hypofibrinolytic state observed in patients with venous thrombosis [3].
• Histidine-rich glycoprotein and changes in the components of the fibrinolytic system after streptokinase therapy in patients with pulmonary thromboembolism [1].

High impact information on HRG

• Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells [4].
• The multicellular inflammatory response to endothelial injury characterized, in part, by the influx of platelets and macrophages, may be associated with HRGP release into the arterial microenvironment [4].
• This release of HRGP may allow smooth muscle cell proliferation and atherogenesis by inhibiting the action of endothelial cell-derived heparinoid substances [4].
• We have shown previously that HRGP binds with high affinity to thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that is a potent inhibitor of angiogenesis [2].
• In contrast to histidine-rich glycoprotein, purified platelet factor 4 prevented inhibition of thrombin by heparin cofactor II in the presence of either heparin or dermatan sulfate at the ratio of 2 micrograms platelet factor 4/micrograms glycosaminoglycan [5].

Chemical compound and disease context of HRG

• Using radial immunodiffusion serum histidine-rich glycoprotein (HRG) levels were measured in acquired immune deficiency syndrome (AIDS) patients, in end-stage renal disease (ESRD) patients after renal transplantation and immunosuppressive steroid therapy, and in asthma and chronic obstructive pulmonary disease (COPD) patients treated with steroids [6].
• Thus, under conditions of local acidosis (e.g. ischemia or hypoxia), HPRG can co-immobilize plasminogen at the cell surface as well as compete for heparin with other proteins such as antithrombin [7].
• We have shown that a fragment released from the central histidine/proline-rich (His/Pro-rich) domain of HRGP blocks endothelial cell migration in vitro and vascularization and growth of murine fibrosarcoma in vivo [8].

Biological context of HRG

• This interaction is mediated by the amino-terminal domain of HRG and results in enhanced phagocytosis of the necrotic cells by a monocytic cell line [9].
• These observations demonstrate that HPRG can act as either a positive or negative effector of Plg activation in vitro and may serve as a modulator of fibrinolysis in vivo [10].
• The interaction of the conserved C-terminal lysine of HPRG with the high affinity lysine binding site of plasminogen is necessary and sufficient to accelerate plasminogen activation [11].
• Modification of lysine residues of HPRG or competitive binding by lysine and anti-fibrinolytic agents containing primary amino groups also inhibits association [12].
• We then examined the nucleotide sequences of all seven exons of the proband's HRG gene [13].

Anatomical context of HRG

• Thus, HRG has the unique property of selectively recognizing necrotic cells and may play an important physiological role in vivo by facilitating the uptake and clearance of necrotic, but not apoptotic, cells by phagocytes [9].
• The binding characteristics of HRGP to T lymphocytes indicate a specific ligand-receptor interaction [14].
• In this study, we show that HRG potentiates the ingestion of apoptotic cells by mature human monocyte-derived macrophages (HMDM) [15].
• HRG bound specifically to apoptotic Jurkat cells and mature HMDM in a saturable and concentration-dependent manner [15].
• HRG was also shown to significantly inhibit both FGF-stimulated and endogenous 3T3 cell DNA synthesis [16].

Associations of HRG with chemical compounds

• Furthermore, blocking studies with various GAG species indicated that only heparin was a potent inhibitor of HRG binding [17].
• In this study we have demonstrated that HRG also binds very strongly, in a heparan sulfate-independent manner, to cytoplasmic ligand(s) exposed in necrotic cells [9].
• Histidine-rich glycoprotein (HRG) is an alpha2-glycoprotein found in mammalian plasma at high concentrations (approximately 150 microg/ml) and is distinguished by its high content of histidine and proline [17].
• HRG binds to most cells primarily via heparan sulphate proteoglycans, binding which is also potentiated by elevated free Zn(2+) levels and low pH [18].
• A reduced susceptibility to inhibition by chloride ions contributed to the higher activation rate of Glu-plasminogen on an HPRG surface [11].

Physical interactions of HRG

• Acceleration of plasminogen activation by tissue plasminogen activator on surface-bound histidine-proline-rich glycoprotein [11].
• Histidine-rich glycoprotein binds to DNA and Fc gamma RI and potentiates the ingestion of apoptotic cells by macrophages [15].
• We have shown that HRGP binds specifically to human T lymphocytes but not sheep erythrocytes and have demonstrated a 56-kDa HRGP-binding protein on the T cell surface which is distinct from the CD2 sheep erythrocyte receptor [19].

Regulatory relationships of HRG

• Soluble HPRG did not significantly influence plasminogen activation [11].
• In contrast, VEGF-induced proliferation was not affected by HRGP or HRGP330, demonstrating the central role of cell migration during tube formation [8].
• Furthermore, HRGP inhibited interleukin 2 receptor expression on activated T cells, causing decreased T cell interferon-gamma release and altered T cell-dependent inhibition of erythropoiesis [19].
• The results suggest that zinc markedly potentiates the binding of HRG to T cells, and that HRG and zinc may play an important role in regulating the adhesion of T cells to other cells and the extracellular matrix [20].
• We conclude that histidine-rich glycoprotein and platelet factor 4 can regulate the antithrombin activity of heparin cofactor II [5].

Other interactions of HRG

• Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1 [2].
• In contrast, HPRG abrogates the stimulatory effects of fibrinogen on Plg activation in solution [10].
• No correlation between HRGP level and t-PA-mediated plasminogen activation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)[3]
• Structurally, HRG is a modular protein consisting of an N-terminal cystatin-like domain (N1N2), a central histidine-rich region (HRR) flanked by proline-rich sequences, and a C-terminal domain [17].
• These data suggest that heparan sulfate is the predominate cell-surface ligand for HRG and that mammalian heparanase is a potential regulator of HRG binding [17].

Analytical, diagnostic and therapeutic context of HRG

• The HRG peaks on crossed immunoelectrophoresis before and after SK infusion were also unchanged [1].
• Complex formation was detected by a specific binding enzyme-linked immunosorbent assay (ELISA) which demonstrated simultaneous binding of fluid-phase Plg and HRGP to TSP adsorbed to microtitration wells [21].
• Using both HRGP affinity chromatography and immunoprecipitation with affinity-purified anti-HRGP IgG, a major 56-kDa HRGP-binding protein in surface labeled T cell lysates was demonstrated [14].
• The amount of plasmin generated by plasma from patients having high levels of HRGP (160% to 280%) was similar to that of a control group having normal levels of HRGP (100% +/- 22%) [3].
• Western blot analysis showed that complement C8, C9, factor D, and S-protein in diluted serum were bound by nylon membrane-immobilized HRG [22].

1. Histidine-rich glycoprotein and changes in the components of the fibrinolytic system after streptokinase therapy in patients with pulmonary thromboembolism. Goodnough, L.T., Saito, H., Bell, W.R., Heimburger, N. Am. J. Hematol. (1985)
2. Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1. Simantov, R., Febbraio, M., Crombie, R., Asch, A.S., Nachman, R.L., Silverstein, R.L. J. Clin. Invest. (2001)
3. Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism. Angles-Cano, E., Gris, J.C., Loyau, S., Schved, J.F. J. Lab. Clin. Med. (1993)
4. Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells. Hajjar, D.P., Boyd, D.B., Harpel, P.C., Nachman, R.L. J. Exp. Med. (1987)
5. Modulation of heparin cofactor II activity by histidine-rich glycoprotein and platelet factor 4. Tollefsen, D.M., Pestka, C.A. J. Clin. Invest. (1985)
6. Serum histidine-rich glycoprotein levels are decreased in acquired immune deficiency syndrome and by steroid therapy. Morgan, W.T. Biochem. Med. Metab. Biol. (1986)
7. Histidine-proline-rich glycoprotein as a plasma pH sensor. Modulation of its interaction with glycosaminoglycans by ph and metals. Borza, D.B., Morgan, W.T. J. Biol. Chem. (1998)
8. Signal transduction in endothelial cells by the angiogenesis inhibitor histidine-rich glycoprotein targets focal adhesions. Lee, C., Dixelius, J., Thulin, A., Kawamura, H., Claesson-Welsh, L., Olsson, A.K. Exp. Cell Res. (2006)
9. Histidine-rich glycoprotein specifically binds to necrotic cells via its amino-terminal domain and facilitates necrotic cell phagocytosis. Jones, A.L., Poon, I.K., Hulett, M.D., Parish, C.R. J. Biol. Chem. (2005)
10. Effects of histidine-proline-rich glycoprotein on plasminogen activation in solution and on surfaces. Borza, D.B., Shipulina, N.V., Morgan, W.T. Blood Coagul. Fibrinolysis (2004)
11. Acceleration of plasminogen activation by tissue plasminogen activator on surface-bound histidine-proline-rich glycoprotein. Borza, D.B., Morgan, W.T. J. Biol. Chem. (1997)
12. Interaction of histidine-proline-rich glycoprotein with plasminogen: effect of ligands, pH, ionic strength, and chemical modification. Saez, C.T., Jansen, G.J., Smith, A., Morgan, W.T. Biochemistry (1995)
13. HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency. Shigekiyo, T., Yoshida, H., Matsumoto, K., Azuma, H., Wakabayashi, S., Saito, S., Fujikawa, K., Koide, T. Blood (1998)
14. Interaction of histidine-rich glycoprotein with human T lymphocytes. Saigo, K., Shatsky, M., Levitt, L.J., Leung, L.K. J. Biol. Chem. (1989)
15. Histidine-rich glycoprotein binds to DNA and Fc gamma RI and potentiates the ingestion of apoptotic cells by macrophages. Gorgani, N.N., Smith, B.A., Kono, D.H., Theofilopoulos, A.N. J. Immunol. (2002)
16. Histidine-rich glycoprotein and platelet factor 4 mask heparan sulfate proteoglycans recognized by acidic and basic fibroblast growth factor. Brown, K.J., Parish, C.R. Biochemistry (1994)
17. Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation. Jones, A.L., Hulett, M.D., Parish, C.R. J. Biol. Chem. (2004)
18. Histidine-rich glycoprotein: A novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems. Jones, A.L., Hulett, M.D., Parish, C.R. Immunol. Cell Biol. (2005)
19. Histidine-rich glycoprotein blocks T cell rosette formation and modulates both T cell activation and immunoregulation. Shatsky, M., Saigo, K., Burdach, S., Leung, L.L., Levitt, L.J. J. Biol. Chem. (1989)
20. Histidine-rich glycoprotein binding to T-cell lines and its effect on T-cell substratum adhesion is strongly potentiated by zinc. Olsen, H.M., Parish, C.R., Altin, J.G. Immunology (1996)
21. Platelet thrombospondin forms a trimolecular complex with plasminogen and histidine-rich glycoprotein. Silverstein, R.L., Leung, L.L., Harpel, P.C., Nachman, R.L. J. Clin. Invest. (1985)
22. Regulation of complement functional efficiency by histidine-rich glycoprotein. Chang, N.S., Leu, R.W., Rummage, J.A., Anderson, J.K., Mole, J.E. Blood (1992)