Pro-oxidant and cytotoxic effects of circulating heme.
Numerous pathologies may involve toxic side effects of free heme and heme-derived iron. Deficiency of the heme-catabolizing enzyme, heme oxygenase-1 (HO-1), in both a human patient and transgenic knockout mice leads to an abundance of circulating heme and damage to vascular endothelium. Although heme can be directly cytotoxic, the present investigations examine the possibility that hemoglobin-derived heme and iron might be indirectly toxic through the generation of oxidized forms of low-density lipoprotein (LDL). In support, hemoglobin in plasma, when oxidized to methemoglobin by oxidants such as leukocyte-derived reactive oxygen, causes oxidative modification of LDL. Heme, released from methemoglobin, catalyzes the oxidation of LDL, which in turn induces endothelial cytolysis primarily caused by lipid hydroperoxides. Exposure of endothelium to sublethal concentrations of this oxidized LDL leads to induction of both HO-1 and ferritin. Similar endothelial cytotoxicity was caused by LDL isolated from plasma of an HO-1-deficient child. Spectral analysis of the child's plasma revealed a substantial oxidation of plasma hemoglobin to methemoglobin. Iron accumulated in the HO-1-deficient child's LDL and several independent assays revealed oxidative modification of the LDL. We conclude that hemoglobin, when oxidized in plasma, can be indirectly cytotoxic through the generation of oxidized LDL by released heme and that, in response, the intracellular defense-HO-1 and ferritin-is induced. These results may be relevant to a variety of disorders-such as renal failure associated with intravascular hemolysis, hemorrhagic injury to the central nervous system, and, perhaps, atherogenesis-in which hemoglobin-derived heme may promote the formation of fatty acid hydroperoxides.
Jeney
Viktória
V
Department of Medicine, University of Debrecen, Hungary.
Balla
József
J
Yachie
Akihiro
A
Varga
Zsuzsa
Z
Vercellotti
Gregory M
GM
Eaton
John W
JW
Balla
György
G
D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003602:Cytotoxicity, Immunologic; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006418:Heme / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology; D051547:Heme Oxygenase-1; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology*; D008054:Lipid Peroxides / Q000378:metabolism / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000502:physiology; D008565:Membrane Proteins; D008706:Methemoglobin / Q000378:metabolism / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology
D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; C099252:oxidized low density lipoprotein; D006418:Heme; D008706:Methemoglobin; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1