title: Oxidation of hemoglobin by lipid hydroperoxide associated with low-density lipoprotein (LDL) and increased cytotoxic effect by LDL oxidation in heme oxygenase-1 (HO-1) deficiency.
abstract: Heme-catalyzed oxidation of low-density lipoprotein (LDL) is one of the relevant mechanisms involved in LDL modification. We previously revealed a substantial oxidation of plasma hemoglobin to methemoglobin and a subsequent heme-catalyzed LDL oxidation generating moieties toxic to endothelium in heme oxygenase-1 (HO-1)-deficiency in human. Drawing upon our previous observation we posited a pathway for oxidation of plasma hemoglobin in the HO-1-deficient child involving LDL-associated lipid hydroperoxide. In support, LDL-associated lipid hydroperoxide oxidized ferrohemoglobin to methemoglobin--known to readily release its heme moieties--in a dose-dependent manner. Repeated heme exposure of the child s LDL further increased its lipid hydroperoxide content within min leading to additional cytotoxic effect on endothelium. Both cytotoxicity and HO-1 inducing ability of the oxidized LDL were strongly dependent on its lipid hydroperoxide content. We wondered if cells of the HO-1-deficient patient were prone to oxidative damage arising from heme-mediated oxidation of LDL. Indeed, we found elevated cytotoxicity induced by heme-catalyzed oxidation of LDL in lymphoblastoid cells derived from the HO-1-deficient patient. We conclude that oxidation of hemoglobin to methemoglobin by LDL-associated lipid hydroperoxide and increased sensitivity of cells of the HO-1-deficient child to stress of oxidized LDL might contribute to the vascular disorders reported earlier.
authors.affiliation: Department of Medicine, University of Debrecen, Debrecen 4012, Hungary.
authors.forename: E
authors.initials: E
authors.lastname: Nagy
authors.forename: V
authors.initials: V
authors.lastname: Jeney
authors.forename: A
authors.initials: A
authors.lastname: Yachie
authors.forename: R P
authors.initials: RP
authors.lastname: Szabó
authors.forename: O
authors.initials: O
authors.lastname: Wagner
authors.forename: G M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: J W
authors.initials: JW
authors.lastname: Eaton
authors.forename: G
authors.initials: G
authors.lastname: Balla
authors.forename: J
authors.initials: J
authors.lastname: Balla
mesh_terms: D049109:Cell Proliferation; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL; D006454:Hemoglobins; D008054:Lipid Peroxides; D012333:RNA, Messenger; D051547:Heme Oxygenase-1