Vallelian, F; Pimenova, T; Pereira, C P; Abraham, B; Mikolajczyk, M G; Schoedon, G; Zenobi, R; Schaer, D J (2008). The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways. Free Radical Biology and Medicine, 45(8):1150-1158.
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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 alpha-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 H(2)O(2)-mediated Hb oxidation results in the formation of covalently stabilized globin multimers, with prominent intramolecular crosslinking between alpha-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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine|
|DDC:||610 Medicine & health|
|Date:||15 August 2008|
|Deposited On:||02 Mar 2009 15:23|
|Last Modified:||23 Nov 2012 14:02|
|Additional Information:||Free text at http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T38-4T2YMWR-2-N&_cdi=4940&_user=5294990&_orig=search&_coverDate=10%2F15%2F2008&_sk=999549991&view=c&wchp=dGLbVtz-zSkWb&md5=244c00d7377f78863a36dec2eefda188&ie=/sdarticle.pdf|
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