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Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet

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Abstract

Strongly pronounced argyrosis caused by adding AgCl to the feed of laboratory rats efficiently mimics the deficiency of ceruloplasmin (CP) ferroxidase activity. Bringing the concentration of AgCl in the feedstuff of lactating rats to 250 mg % and keeping their progeny (Ag-rats) for 3 months on the same silver-containing feed provided the serum iron content 1.4 times lower than that in the control group. Besides, the ferroxidase activity of CP dropped to zero. In CP purified from sera of Ag-rats two copper ions were substituted with two silver ions. Using rat models of both post-hemorrhagic and hemolytic anemia we showed that the deficiency of CP ferroxidase activity in Ag-rats affects the iron content in serum, though does not prevent the recovery of hemoglobin level accompanied by exhaustion of iron caches in liver and spleen. When apo-lactoferrin (apo-LF) was administered to Ag-rats suffering from either post-hemorrhagic or hemolytic anemia, both hemoglobin and serum iron were restored more rapidly than in the control animals. In independent experiments Ag-rats were compared with those fed on regular diet and the former displayed a prolonged 3-day stabilization of hypoxia-inducible factors 1 and 2 alpha (HIF-1a and HIF-2a) along with an increased serum concentration of erythropoietin. Introduction to Ag-rats of active CP separately or together with apo-LF reduced that effect to 1 day only. It is concluded that saturation of apo-LF with iron, provided by active CP, can strongly affect its protective capacity.

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Abbreviations

Ag-rats:

Rats with AgCl-diet

Apo-LF:

Apo-form LF

CP:

Ceruloplasmin

EPO:

Erythropoietin

HIF-1a:

Hypoxia-inducible factor-1 alpha

HIF-2a:

Hypoxia-inducible factor-2 alpha

LF:

Lactoferrin

TF:

Transferrin

References

  • Aisen P, Listowsky I (1980) Iron transport and storage proteins. Annu Rev Biochem 49:357–393

    Article  CAS  PubMed  Google Scholar 

  • Anderson NL, Nance SL, Pearson TW et al (1982) Specific antiserum staining of two-dimensional electrophoretic patterns of human plasma proteins immobilized on nitrocellulose. Electrophoresis 3:135–142

    Article  CAS  Google Scholar 

  • Anderson GJ, Murphy TL, Cowley L et al (1998) Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse. Genomics 48:34–39

    Article  CAS  PubMed  Google Scholar 

  • Birgens HS (1994) The monocytic receptor for lactoferrin and its involvement in lactoferrin-mediated iron transport. Adv Exp Med Biol 357:99–109

    Article  CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Cervello V, Barabini E (1894) Sul potere ematogeno dei metallic pesanti. Tipogr Ed Tempo, Palermo

    Google Scholar 

  • Cherukuri S, Potla R, Sarkar J et al (2005) Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab 2:309–319

    Article  CAS  PubMed  Google Scholar 

  • Cutone A, Frioni A, Berlutti F et al (2014) Lactoferrin prevents LPS-induced decrease of the iron exporter ferroportin in human monocytes/macrophages. Biometals 27:807–813

    Article  CAS  PubMed  Google Scholar 

  • Davis BJ (1964) Disk elecrtophoresis. II. Method and application to human serum proteins. Ann N Y Acad Sci 121:404–427

    Article  CAS  PubMed  Google Scholar 

  • De Domenico I, Ward DMcV, di Patti MCB et al (2007) Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J 26:2823–2831

    Article  PubMed  PubMed Central  Google Scholar 

  • Erel O (1998) Automated measurement of serum ferroxidase activity. Clin Chem 44:2313–2319

    CAS  PubMed  Google Scholar 

  • Fling SP, Gregerson DS (1986) Peptide and protein molecular weight determination by electrophoresis using a high-molarity tris buffer system without urea. Anal Biochem 155:83–88

    Article  CAS  PubMed  Google Scholar 

  • Gruen LC (1975) Interaction of amino acids with silver(I) ions. Biochim Biophys Acta 386:270–274

    Article  CAS  PubMed  Google Scholar 

  • Harris ZL, Durley AP, Man TK et al (1999) Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. PNAS 96:10812–10817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hart EB, Steenbock H, Waddell J et al (1928) Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Biol Chem 77:97–812

    Google Scholar 

  • Hodgson GS (1973) Properties of haemopoietic stem cells in phenylhydrazine treated mice. Cell Tissue Kinet 6:199–208

    CAS  PubMed  Google Scholar 

  • Jeong SY, David S (2003) GPI-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J Biol Chem 278:27144–27148

    Article  CAS  PubMed  Google Scholar 

  • Lahey ME, Gubler CJ, Chase MS et al (1952) Studies on copper metabolism. II. Hematologic manifestations of copper deficiency in swine. Blood 7:1053–1074

    CAS  PubMed  Google Scholar 

  • Laurell CB (1967) Quantitative estimation of proteins by electrophoresis in antibody-containing agarose gel. In: Peeters H (ed) Protides of the biological fluids. Elsevier, Amsterdam

    Google Scholar 

  • Masson PL (1970) In: Arscia SA (ed) Proteine des Secretions Externes et des Leucocytes Neutrophiles. La Lactoferrine, Brussels

    Google Scholar 

  • Mendini L (1862) Di un rimedio per l’amenorrea et di altro per la sordita ipostenica. Gazz Med Ital Prov Venete 5:36–37

    Google Scholar 

  • Nguyen DN, Jiang P, Stensballe A et al (2016) Bovine lactoferrin regulates cell survival, apoptosis and inflammation in intestinal epithelial cells and preterm pig intestine. J Proteom 139:95–102

    Article  CAS  Google Scholar 

  • Noyer M, Dwulet FE, Hao YL, Putnam FW (1980) Purification and characterization of undergraded human ceruloplasmin. Anal Biochem 102:450–458

  • Park Y-G, Moon J-H, Park S-Y (2014) Lactoferrin from bovine colostrum regulates prolyl hydroxylase 2 activity and prevents prion protein-mediated neuronal cell damage via cellular prion protein. Neuroscience 274:187–197

    Article  CAS  PubMed  Google Scholar 

  • Pribyl T, Schreiber V, Jahodová J (1980) Inhibition of rat serum polyphenoloxidase activity by silver ions abolished by administration of copper ions. Folia Biol (Praha) 261:47–52

    Google Scholar 

  • Pulina MO, Sokolov AV, Zakharova ET et al (2010) Effect of lactoferrin on consequences of acute experimental hemorrhagic anemia in rats. Bull Exp Biol Med 149:219–222

    Article  CAS  PubMed  Google Scholar 

  • Sabatucci A, Vachette P, Vasilyev VB et al (2007) Structural characterization of the ceruloplasmin: lactoferrin complex in solution. J Mol Biol 371:1038–1046

    Article  CAS  PubMed  Google Scholar 

  • Samygina VR, Sokolov AV, Pulina MO et al (2008) X-ray diffraction study of highly purified human ceruloplasmin. Crystallogr Rep 53:655–662

    Article  CAS  Google Scholar 

  • Samygina VR, Sokolov AV, Bourenkov G et al (2013) Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins. PLoS One 8:e67145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scortegagna M, Ding K, Zhang Q et al (2005) HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood 105:3133–3140

    Article  CAS  PubMed  Google Scholar 

  • Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634

    Article  CAS  PubMed  Google Scholar 

  • Shah YM, Xie L (2014) Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology 146:630–642

    Article  CAS  PubMed  Google Scholar 

  • Shavlovski MM, Chebotar NA, Konopistseva LA et al (1995) Embryotoxicity of silver ions is diminished by ceruloplasmin—further evidence for its role in the transport of copper. Biometals 8:122–128

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Pulina MO, Zakharova ET et al (2005a) Effect of lactoferrin on the ferroxidase activity of ceruloplasmin. Biochemistry (Moscow) 70:1015–1019

    Article  CAS  Google Scholar 

  • Sokolov AV, Zakharova ET, Shavlovskii MM et al (2005b) Isolation of stable human ceruloplasmin and its interaction with salmon protamine. Bioorg Khim 31:269–279

    CAS  PubMed  Google Scholar 

  • Sokolov AV, Pulina MO, Kristiyan AV et al (2006a) A study of recombinant human lactoferrin secreted in milk of transgenic mice. Dokl Biochem Biophys 411:336–368

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Pulina MO, Zakharova ET et al (2006b) Identification and isolation from breast milk of ceruloplasmin–lactoferrin complex. Biochemistry (Mosc) 71:160–166

    Article  CAS  Google Scholar 

  • Sokolov AV, Ageeva KV, Pulina MO et al (2009) Effect of lactoferrin on oxidative features of ceruloplasmin. Biometals 22:521–529

    Article  CAS  PubMed  Google Scholar 

  • Sokolov AV, Kostevich VA, Romanico DN et al (2012) Two-stage method for purification of ceruloplasmin based on its interaction with neomycin. Biochemistry (Mosc) 77:631–638

    Article  CAS  Google Scholar 

  • Topham RW, Frieden E (1970) Identification and purification of a non-ceruloplasmin ferroxidase of human serum. J Biol Chem 245:6698–6705

    CAS  PubMed  Google Scholar 

  • van Snick JL, Masson PL, Heremans JF (1974) The involvement of lactoferrin in the hyposideremia of acute inflammation. J Exp Med 140:1068–1084

    Article  PubMed  PubMed Central  Google Scholar 

  • Vulpe CD, Kuo YM, Murphy TL et al (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21:195–199

    Article  CAS  PubMed  Google Scholar 

  • Warnecke C, Zaborowska Z, Kurreck J et al (2004) Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells. FASEB J 18:1462–1464

    CAS  PubMed  Google Scholar 

  • Yoshida K, Furihata K, Takeda S et al (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9:267–272

    Article  CAS  PubMed  Google Scholar 

  • Zaitsev VN, Zaitseva I, Papiz M et al (1999) An X-ray crystallographic study of the binding center of azide inhibitor and organic substrates of ceruloplasmin, a multi-copper oxidase in plasma. J Biol Inorg Chem 4:579–587

    Article  CAS  PubMed  Google Scholar 

  • Zakharova ET, Vasil’ev VB, Gorbunova VN, Shavlovskiĭ MM (1983) Isolation and physico-chemical properties of rat ceruloplasmin. Biokhimiia 48:1709–1720

    CAS  PubMed  Google Scholar 

  • Zakharova ET, Shavlovski MM, Bass MG et al (2000) Interaction of lactoferrin with ceruloplasmin. Arch Biochem Biophys 374:222–228

    Article  CAS  PubMed  Google Scholar 

  • Zakharova ET, Kostevich VA, Sokolov AV et al (2012) Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha. Biometals 25:1247–1259

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by RFBR Grants 13-04-01191, 15-04-03620 and Grant MK-5074.2016.4.

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Authors and Affiliations

  1. Institute for Experimental Medicine, Pavlov street 12, Saint Petersburg, 197376, Russia

    Valeria A. Kostevich, Alexey V. Sokolov, Stanislav O. Kozlov, Anna Yu. Vlasenko, Nikolay N. Kolmakov, Elena T. Zakharova & Vadim B. Vasilyev

  2. Saint-Petersburg State University, Mendeleevskaya line, Saint Petersburg, 199000, Russia

    Alexey V. Sokolov & Vadim B. Vasilyev

Authors
  1. Valeria A. Kostevich
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  2. Alexey V. Sokolov
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  3. Stanislav O. Kozlov
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  4. Anna Yu. Vlasenko
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  5. Nikolay N. Kolmakov
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  6. Elena T. Zakharova
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  7. Vadim B. Vasilyev
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Correspondence to Alexey V. Sokolov.

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Kostevich, V.A., Sokolov, A.V., Kozlov, S.O. et al. Functional link between ferroxidase activity of ceruloplasmin and protective effect of apo-lactoferrin: studying rats kept on a silver chloride diet. Biometals 29, 691–704 (2016). https://doi.org/10.1007/s10534-016-9944-2

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  • DOI: https://doi.org/10.1007/s10534-016-9944-2

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