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.
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.
Nagy
E
E
Department of Medicine, University of Debrecen, Debrecen 4012, Hungary.
Jeney
V
V
Yachie
A
A
Szabó
R P
RP
Wagner
O
O
Vercellotti
G M
GM
Eaton
J W
JW
Balla
G
G
Balla
J
J
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
D008078:Cholesterol, LDL; D006454:Hemoglobins; D008054:Lipid Peroxides; D012333:RNA, Messenger; D051547:Heme Oxygenase-1