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Oxidative Medicine and Cellular Longevity
Volume 2013, Article ID 676425, 13 pages
Research Article

Atherogenesis May Involve the Prooxidant and Proinflammatory Effects of Ferryl Hemoglobin

1MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, 4012 Debrecen, Hungary
2Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
3Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
4Department of Pediatrics, University of Debrecen, 4012 Debrecen, Hungary

Received 27 February 2013; Accepted 23 April 2013

Academic Editor: Gregory M. Vercellotti

Copyright © 2013 László Potor et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Oxidized cell-free hemoglobin (Hb), including covalently cross-linked Hb multimers, is present in advanced atherosclerotic lesions. Oxidation of Hb produces methemoglobin ( ) and ferryl hemoglobin ( ). Ferryl iron is unstable and can return to the state by reacting with specific amino acids of the globin chains. In these reactions globin radicals are produced followed by termination reactions yielding covalently cross-linked Hb multimers. Despite the evanescent nature of the ferryl state, herein we refer to this oxidized Hb as “ferryl Hb.” Our aim in this work was to study formation and biological effects of ferrylHb. We demonstrate that ferrylHb, like metHb, can release its heme group, leading to sensitization of endothelial cells (ECs) to oxidant-mediated killing and to oxidation of low-density lipoprotein (LDL). Furthermore, we observed that both oxidized LDL and lipids derived from human atherosclerotic lesions trigger Hb oxidation and subsequent production of covalently cross-linked ferrylHb multimers. Previously we showed that ferrylHb disrupts EC monolayer integrity and induces expression of inflammatory cell adhesion molecules. Here we show that when exposed to ferrylHb, EC monolayers exhibit increased permeability and enhanced monocyte adhesion. Taken together, interactions between cell-free Hb and atheroma lipids engage in a vicious cycle, amplifying oxidation of plaque lipids and Hb. These processes trigger EC activation and cytotoxicity.