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Blood, 12 March 2009, Vol. 113, No. 11, pp. 2578-2586. Prepublished online as a Blood First Edition Paper on January 8, 2009; DOI 10.1182/blood-2008-08-174466. This Article Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2008-08-174466v1 113/11/2578    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Buehler, P. W Articles by Schaer, D. J. Search for Related Content PubMed PubMed Citation Articles by Buehler, P. W Articles by Schaer, D. J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 18, 2008 Accepted December 22, 2008 Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification Paul W Buehler, Bindu Abraham, Florence Vallelian, Charlotte Linnemayr, Claudia P. Pereira, John F. Cipollo, Yiping Jia, Malgorzata Mikolajczyk, Felicitas S. Boretti, Gabriele Schoedon, Abdu I. Alayash, and Dominik J. Schaer* Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Bethesda, MD, United States Division of Internal Medicine, Inflammation Research, University of Zurich, Zurich, Switzerland Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland * Corresponding author; email: dominik.schaer{at}usz.ch. Detoxification and clearance of extracellular hemoglobin (Hb) has been attributed to its removal by the CD163 scavenger receptor pathway. However, even low level hydrogen peroxide (H2O2) exposure irreversibly modifies Hb and severely impairs Hb endocytosis by CD163. We show here that when Hb is bound to the high affinity Hb scavenger protein haptoglobin (Hp), the complex protects Hb from structural modification by preventing globin crosslinks and oxidations of amino acids in critical regions of the globin chain (e.g. Trp15, Cys93 and Cys112). As a result of this structural stabilization, H2O2 exposed Hb-Hp binds to CD163 with the same affinity as non-oxidized complex. Endocytosis and lysosomal translocation of oxidized Hb-Hp by CD163 expressing cells were found to be as efficient as with non-oxidized complex. Hp complex formation did not alter Hb's ability to consume added H2O2 by redox cycling suggesting that within the complex the oxidative radical burden is shifted to Hp. We provide structural and functional evidence that Hp protects Hb when oxidatively challenged with H2O2 preserving CD163 mediated Hb clearance under oxidative stress conditions. Additionally, our data provides in vivo evidence that unprotected Hb is oxidatively modified within extra-vascular compartments consistent with our in vitro findings. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Kapralov, I. I. Vlasova, W. Feng, A. Maeda, K. Walson, V. A. Tyurin, Z. Huang, R. K. Aneja, J. Carcillo, H. Bayir, et al. Peroxidase Activity of Hemoglobin{middle dot}Haptoglobin Complexes: COVALENT AGGREGATION AND OXIDATIVE STRESS IN PLASMA AND MACROPHAGES J. Biol. Chem., October 30, 2009; 284(44): 30395 - 30407. [Abstract] [Full Text] [PDF] F. Crea and F. Andreotti The unstable plaque: a broken balance Eur. Heart J., August 1, 2009; 30(15): 1821 - 1823. [Full Text] [PDF] M. J. Nielsen and S. K. Moestrup Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging Blood, July 23, 2009; 114(4): 764 - 771. [Abstract] [Full Text] [PDF]

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