title: Atherogenesis may involve the prooxidant and proinflammatory effects of ferryl hemoglobin.
abstract: Oxidized cell-free hemoglobin (Hb), including covalently cross-linked Hb multimers, is present in advanced atherosclerotic lesions. Oxidation of Hb produces methemoglobin (Fe(3+)) and ferryl hemoglobin (Fe(4+) = O(2-)). Ferryl iron is unstable and can return to the Fe(3+) 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.
authors.affiliation: MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, 4012 Debrecen, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Potor
authors.forename: Emese
authors.initials: E
authors.lastname: Bányai
authors.forename: Gergely
authors.initials: G
authors.lastname: Becs
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.forename: György
authors.initials: G
authors.lastname: Balla
authors.forename: József
authors.initials: J
authors.lastname: Balla
authors.forename: Viktória
authors.initials: V
authors.lastname: Jeney
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006242:Haptoglobins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008077:Lipoproteins, LDL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D003432:Cross-Linking Reagents; D006242:Haptoglobins; D006454:Hemoglobins; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D016877:Oxidants; C517773:ferrylhemoglobin; C099252:oxidized low density lipoprotein; D005293:Ferritins; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; D005978:Glutathione