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Role of Haptoglobin in Abdominal Aortic Aneurysm

Chapter

Abstract

Haptoglobin (abbreviated as Hp) is a plasmatic protein encoded by the HP gene (OMIM*140100, gene map locus 16q22.1). Its main function in blood plasma is binding free hemoglobin (Hb) released from erythrocytes with high affinity and thereby inhibiting its oxidative activity. The Hp-Hb complex is then removed by the reticuloendothelial system (mostly the spleen). Hp is widely used in clinical settings where the Hp assay is implemented to screen for and monitor intravascular hemolytic anemia [1]. In intravascular hemolytic anemia, free Hb is released into the circulation, and hence Hp binds the Hb. This causes a decline in Hp levels. Conversely, in extravascular hemolysis, the reticuloendothelial system, especiallysplenic monocytes, phagocytose the erythrocytes, and Hb is not released into the circulation; hence, the Hp levels are normal. Thus, Hp is a potent antioxidant playing a scavenging role for the toxic free Hb that accumulates during acute-phase inflammatory reactions [1]. However, importantly, Hp also exerts a direct angiogenic, antiinflammatory, and immunomodulatory function in extravascular tissues and body fluids. In fact, in response to various stimuli, Hp is able to migrate through vessel walls and is expressed in different tissues [2]. Furthermore, Hp can be released from neutrophil granulocytes at sites of injury or inflammation and locally dampens tissue damage [3]. Hp receptors include CD163 expressed on the monocyte-macrophage system and CD11b (CR3) found on granulocytes, natural killer cells, and in small lymphocyte subpopulations [4, 5]. Hp has also been shown to bind to the majority of CD4+ and CD8+ T cells, directly inhibiting their proliferation and modifying the T helper (Th) Th1/Th2 balance [6]. Notably, Hp inhibits the capacity of epidermal Langerhans cells to activate naive T cells, and abundant Hp has been detected in cytoplasmic compartments of Langerhans cells and in neutrophils [7, 8]. Also, Hp binds to mast cells through another, yet unidentified receptor, possibly modulating their function [9]. Lastly, HDL particles can become proinflammatory through direct interactions of Hp-Hb complexes with apolipoprotein A1 [10].

Keywords

Abdominal Aortic Aneurysm Abdominal Aortic Aneurysm High Density Lipoprotein Particle Unidentified Receptor Abdominal Aortic Aneurysm Repair 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42:1589–600.PubMedGoogle Scholar
  2. 2.
    Yang F, Friedrichs WE, Navarijo-Ashbaugh AL, de Graffenried LA, Bowman BH, Coalson JJ. Cell type-specific and inflammatory-induced expression of haptoglobin gene in lung. Lab Invest. 1995;73:433–40.PubMedGoogle Scholar
  3. 3.
    Theilgaard-Monch K, Jacobsen LC, Nielsen MJ, et al. Haptoglobin is synthesized during granulocyte differentiation, stored in specific granules, and released by neutrophils in response to activation. Blood. 2006;108:353–61.PubMedCrossRefGoogle Scholar
  4. 4.
    Kristiansen M, Graversen JH, Jacobsen C, et al. Identification of the haemoglobin scavenger receptor. Nature. 2001;409:198–201.PubMedCrossRefGoogle Scholar
  5. 5.
    El Ghmati SM, Van Hoeyveld EM, Van Strijp JAG, Ceuppens JL, Stevens EAM. Identification of haptoglobin as an alternative ligand for CD11b/CD18. J Immunol. 1996;156:2542–52.PubMedGoogle Scholar
  6. 6.
    Arredouani M, Matthijs P, Van Hoeyveld E, et al. Haptoglobin directly affects T cells and suppresses T helper cell type 2 cytokine release. Immunology. 2003;108:144–51.PubMedCrossRefGoogle Scholar
  7. 7.
    Xie Y, Li Y, Zhang Q, Stiller MJ, Albert Wang C-L, Wayne Streilein J. Haptoglobin is a natural regulator of Langerhans cell function in the skin. J Dermatol Sci. 2000;24:25–73.PubMedCrossRefGoogle Scholar
  8. 8.
    Wagner L, Gessl A, Parzer SB, Base W, Waldhäusl W, Pasternack MS. Haptoglobin phenotyping by newly developed monoclonal antibodies. Demonstration of haptoglobin uptake into peripheral blood neutrophils and monocytes. J Immunol. 1996;156:1989–96.PubMedGoogle Scholar
  9. 9.
    El Ghmati SM, Arredouani M, Van Hoeyveld EM, Ceuppens JL, Stevens EA. Haptoglobin interacts with the human mast cell line HMC-1 and inhibits its spontaneous proliferation. Scand J Immunol. 2002;55:352–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Watanabe J, Grijalva V, Hama S, et al. Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein. J Biol Chem. 2009;284:18292–301.PubMedCrossRefGoogle Scholar
  11. 11.
    Maeda N, Yang F, Barnett DR, Bowman BH, Smithies O. Duplication within the haptoglobin Hp2 gene. Nature. 1984;309:131–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Asakawa J, Kodaira M, Nakamura N, Satoh C, Fujita M. Chimerism in humans after intragenic recombination at the haptoglobin locus during early embryogenesis. Proc Natl Acad Sci USA. 1999;96:10314–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Delanghe JR, Langlois MR, De Buyzere ML. Haptoglobin polymorphism: a key factor in the proatherogenic role of B cells? Atherosclerosis. 2011;217(1):80–2.PubMedCrossRefGoogle Scholar
  14. 14.
    Langlois M, Delanghe J, Philippé J. Distribution of lymphocyte subsets in bone marrow and peripheral blood is associated with haptoglobin type. Binding of haptoglobin to the B-cell lectin CD22. Eur J Clin Chem Clin Biochem. 1997;35:199–205.PubMedGoogle Scholar
  15. 15.
    Robertson AK, Hansson GK. T cells in atherosclerosis. For better or for worse? Arterioscler Thromb Vasc Biol. 2006;26:2421–32.PubMedCrossRefGoogle Scholar
  16. 16.
    Brouwers A, Langlois M, Delanghe J, et al. Oxidized low-density lipoprotein, iron stores, and haptoglobin polymorphism. Atherosclerosis. 2004;176:189–95.PubMedCrossRefGoogle Scholar
  17. 17.
    Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129–38.PubMedCrossRefGoogle Scholar
  18. 18.
    Langlois MR, Martin M-E, Boelaert JR, et al. The haptoglobin 2–2 phenotype affects serum markers of iron status in healthy males. Clin Chem. 2000;46:1619–25.PubMedGoogle Scholar
  19. 19.
    Levy AP, Levy JE, Kalet-Litman S, et al. Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol. 2007;27:134–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Guetta J, Strauss M, Levy NS, Fahoum L, Levy AP. Haptoglobin genotype modulates the balance of Th1/Th2 cytokines produced by macrophages exposed to free hemoglobin. Atherosclerosis. 2007;191:48–53.PubMedCrossRefGoogle Scholar
  21. 21.
    Grange JJ, Davis V, Baxter BT. Pathogenesis of abdominal aortic aneurysm: an update and look toward the future. Cardiovasc Surg. 1997;5:256–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Wassef M, Baxter BT, Chisholm RL, Dalman RL, Fillinger MF, Heinecke J, et al. Pathogenesis of abdominal aortic aneurysms: a multidisciplinary research program supported by the National Heart, Lung, and Blood Institute. J Vasc Surg. 2001;34:730–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Powell JT, Muller BR, Greenhalgh RM. Acute phase proteins in patients with abdominal aortic aneurysms. J Cardiovasc Surg (Torino). 1987;28:528–30.Google Scholar
  24. 24.
    Juvonen J, Surcel HM, Satta J, Teppo AM, Bloigu A, Syrjala H, et al. Elevated circulating levels of inflammatory cytokines in patients with abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 1997;17:2843–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Lee AJ, Fowkes FG, Lowe GD, Rumley A. Haemostatic factors, atherosclerosis and risk of abdominal aortic aneurysm. Blood Coagul Fibrinolysis. 1996;7:695–701.PubMedCrossRefGoogle Scholar
  26. 26.
    Domanovits H, Schillinger M, Mullner M, Holzenbein T, Janata K, Bayegan K, et al. Acute phase reactants in patients with abdominal aortic aneurysm. Atherosclerosis. 2002;163:297–302.PubMedCrossRefGoogle Scholar
  27. 27.
    Singh K, Bonaa KH, Jacobsen BK, Bjork L, Solberg S. Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study: the Tromso Study. Am J Epidemiol. 2001;154:236–44.PubMedCrossRefGoogle Scholar
  28. 28.
    Rohde LE, Arroyo LH, Rifai N, Creager MA, Libby P, Ridker PM, et al. Plasma concentrations of interleukin-6 and abdominal aortic diameter among subjects without aortic dilatation. Arterioscler Thromb Vasc Biol. 1999;19:1695–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Vainas T, Lubbers T, Stassen FR, Herngreen SB, van Dieijen-Visser MP, Bruggeman CA, et al. Serum C-reactive protein level is associated with abdominal aortic aneurysm size and may be produced by aneurysmal tissue. Circulation. 2003;107:1103–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Norrgård O, Fröhlander N, Beckman G, Angqvist KA. Association between haptoglobin groups and aortic abdominal aneurysms. Hum Hered. 1984;34:166–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Powell JT, Bashir A, Dawson S, Vine N, Henney AM, Humphries SE, et al. Genetic variation on chromosome 16 is associated with abdominal aortic aneurysm. Clin Sci (Lond). 1990;78:13–6.Google Scholar
  32. 32.
    Adamson J, Powell JT, Greenhalgh RM. Selection for screening for familial aortic aneurysms. Br J Surg. 1992;79:897–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Wiernicki I, Gutowski P, Ciechanowski K, Millo B, Wieczorek P, Cnotliwy M, et al. Abdominal aortic aneurysm: association between haptoglobin phenotypes, elastase activity, and neutrophil count in the peripheral blood. Vasc Surg. 2001;35:345–50.PubMedCrossRefGoogle Scholar
  34. 34.
    Wiernicki I, Safranow K, Baranowska-Bosiacka I, Piatek J, Gutowski P. Haptoglobin 2–1 phenotype predicts rapid growth of abdominal aortic aneurysms. J Vasc Surg. 2010;52:691–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Pan JP, Cheng TM, Shih CC, Chiang SC, Chou SC, Mao SJ, et al. Haptoglobin phenotypes and plasma haptoglobin levels in patients with abdominal aortic aneurysm. J Vasc Surg. 2011;53:1189–94.PubMedCrossRefGoogle Scholar
  36. 36.
    Engström G, Börner G, Lindblad B, Janzon L, Lindgärde F. Incidence of fatal or repaired abdominal aortic aneurysm in relation to inflammation-sensitive plasma proteins. Arterioscler Thromb Vasc Biol. 2004;24:337–41.PubMedCrossRefGoogle Scholar
  37. 37.
    Oldenburg HS, Siroen MP, Boelens PG, Sluijter BJ, Pruitt JH, Naseri AH, et al. Aortic aneurysm repair is associated with a lower inflammatory response compared with surgery for inflammatory bowel disease. Eur Surg Res. 2004;36:266–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Gamberi T, Puglia M, Guidi F, Magherini F, Bini L, Marzocchini R, et al. A proteomic approach to identify plasma proteins in patients with abdominal aortic aneurysm. Mol Biosyst. 2011;7:2855–62.PubMedCrossRefGoogle Scholar
  39. 39.
    Napolioni V. Regarding “haptoglobin 2–1 phenotype predicts rapid growth of abdominal aortic aneurysms”. J Vasc Surg. 2011;53:266–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Comings DE, MacMurray JP. Molecular heterosis: a review. Mol Genet Metab. 2000;71:19–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Papp M, Foldi I, Nemes E, Udvardy M, Harsfalvi J, Altorjay I, et al. Haptoglobin polymorphism: a novel genetic risk factor for celiac disease development and its clinical manifestations. Clin Chem. 2008;54(4):697–704.PubMedCrossRefGoogle Scholar
  42. 42.
    Braeckman L, De Bacquer D, Delanghe J, Claeys L, De Backer G. Associations between haptoglobin polymorphism, lipids, lipoproteins and inflammatory variables. Atherosclerosis. 1999;143:383–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Cigliano L, Pugliese CR, Spagnuolo MS, Palumbo R, Abrescia P. Haptoglobin binds the antiatherogenic protein apolipoprotein E – impairment of apolipoprotein E stimulation of both lecithin:cholesterol acyltransferase activity and cholesterol uptake by hepatocytes. FEBS J. 2009;276:6158–71.PubMedCrossRefGoogle Scholar
  44. 44.
    Philippidis P, Mason JC, Evans BJ, Nadra I, Taylor KM, Haskard DO, et al. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res. 2004;94:119–26.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.School of Biosciences and BiotechnologiesUniversity of CamerinoCamerinoItaly

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