The reaction of hydrogen peroxide with hemoglobin induces extensive α-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways

被引：63

作者：

Vallelian, Florence ^{[2
]}

Pimenova, Tatiana ^{[3
]}

Pereira, Claudia P. ^{[2
]}

Abraham, Bindu ^{[1
]}

Mikolajczyk, Malgorzata G. ^{[1
]}

Schoedon, Gabriele ^{[2
]}

Zenobi, Renato ^{[3
]}

Alayash, Abdu I. ^{[1
]}

Buehler, Paul W. ^{[1
]}

Schaer, Dominik J. ^{[1
,2
]}

机构：

[1] US FDA, Lab Biochem & Vasc Biol, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA

[2] Univ Zurich, Internal Med Res Unit, Zurich, Switzerland

[3] Swiss Fed Inst Technol, Dept Chem & Appl Biosci, Zurich, Switzerland

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2008年 / 45卷 / 08期

基金：

瑞士国家科学基金会;

关键词：

Hemoglobin; Haptoglobin; CD163; Hydrogen peroxide; Oxidative stress;

D O I：

10.1016/j.freeradbiomed.2008.07.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cell-free hemoglobin (Hb) enhances the oxidation-related toxicity associated with inflammation, ischemia, and hemolytic disorders. Hb is highly vulnerable to oxidative damage, and irreversible structural changes involving iron/heme oxidation, heme-adduct products, and amino acid oxidation have been reported. Specific structural features of Hb, such as unconstrained a-chains and molecular size, determine the efficiency of interactions between the endogenous Hb scavengers haptoglobin (Hp) and CD163. Using HPLC, mass spectrometry, and Western blotting, we show that H2O2-mediated Hb oxidation results in the formation of covalently stabilized globin multimers, with prominent intramolecular crosslinking between a-globin chains. These structural alterations are associated with reduced Hp binding, reduced CD163 interaction, and severely impaired endocytosis of oxidized Hb by the Hp-CD163 pathway. As a result, when exposed to oxidized Hb, CD163-positive HEK293 cells and human macrophages do not increase hemeoxygenase-1 (HO-1) expression, the physiological anti-oxidative macrophage response to Hb exposure. Failed Hb clearance, inadequate HO-1 expression, and the subsequent accumulation of oxidatively damaged Hb species might thus contribute to pathologies related to oxidative stress. (C) 2008 Elsevier Inc. All rights reserved.

引用

页码：1150 / 1158

页数：9

共 38 条

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