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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 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 Citation Map 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. Related Collections Red Cells, Iron, and Erythropoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification Paul W. Buehler1, Bindu Abraham1, Florence Vallelian2, Charlotte Linnemayr2, Claudia P. Pereira2, John F. Cipollo1, Yiping Jia1, Malgorzata Mikolajczyk1, Felicitas S. Boretti3, Gabriele Schoedon2, Abdu I. Alayash1, and Dominik J. Schaer2 1 Center for Biologics Evaluation and Research (CBER), US Food and Drug Administration (FDA), Washington, DC; and 2 Division of Internal Medicine, Inflammation Research and 3 Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland Detoxification and clearance of extracellular hemoglobin (Hb) have 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 cross-links and oxidations of amino acids in critical regions of the β-globin chain (eg, Trp15, Cys93, and Cys112). As a result of this structural stabilization, H2O2-exposed Hb-Hp binds to CD163 with the same affinity as nonoxidized complex. Endocytosis and lysosomal translocation of oxidized Hb-Hp by CD163-expressing cells were found to be as efficient as with nonoxidized 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. In addition, our data provide in vivo evidence that unbound Hb is oxidatively modified within extravascular 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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