title: Red cells, hemoglobin, heme, iron, and atherogenesis.
abstract: OBJECTIVE
  We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis.
  
  
  RESULTS
  We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIV=O). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity.
  
  
  CONCLUSIONS
  The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri- and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. These events amplify the endothelial cell cytotoxicity of plaque components.
authors.affiliation: Hemostasis, Thrombosis and Vascular Biology Research Group, Hungarian Academy of Sciences, Debrecen, Hungary.
authors.forename: Emoke
authors.initials: E
authors.lastname: Nagy
authors.forename: John W
authors.initials: JW
authors.lastname: Eaton
authors.forename: Viktória
authors.initials: V
authors.lastname: Jeney
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Varga
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Galajda
authors.forename: József
authors.initials: J
authors.lastname: Szentmiklósi
authors.forename: Gábor
authors.initials: G
authors.lastname: Méhes
authors.forename: Tamás
authors.initials: T
authors.lastname: Csonka
authors.forename: Ann
authors.initials: A
authors.lastname: Smith
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: György
authors.initials: G
authors.lastname: Balla
authors.forename: József
authors.initials: J
authors.lastname: Balla
mesh_terms: D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood* / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006242:Haptoglobins / Q000378:metabolism; D006406:Hematoma / Q000097:blood* / Q000473:pathology; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000097:blood; D006454:Hemoglobins / Q000378:metabolism*; D006461:Hemolysis; D006466:Hemopexin / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000097:blood*; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008706:Methemoglobin / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D008077:Lipoproteins, LDL; C517773:ferrylhemoglobin; D014443:Tyrosine; D006418:Heme; D008706:Methemoglobin; D006466:Hemopexin; C007543:dityrosine; D007501:Iron; D005979:Glutathione Peroxidase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D005978:Glutathione