Pro-oxidant and cytotoxic effects of circulating heme

Viktória Jeney, József Balla, Akihiro Yachie, Zsuzsa Varga, Gregory M. Vercellotti, John W. Eaton, György Balla

Research output: Contribution to journalArticle

424 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)879-887
Number of pages9
JournalBlood
Volume100
Issue number3
DOIs
Publication statusPublished - Aug 1 2002

Fingerprint

Heme
Reactive Oxygen Species
Heme Oxygenase-1
LDL Lipoproteins
Hemoglobins
Methemoglobin
Plasmas
Iron
Lipid Peroxides
Poisons
Ferritins
Oxidation
Vascular Endothelium
Neurology
Pathology
Cytotoxicity
Hemolysis
Oxidants
Knockout Mice
Spectrum analysis

ASJC Scopus subject areas

  • Hematology

Cite this

Pro-oxidant and cytotoxic effects of circulating heme. / Jeney, Viktória; Balla, József; Yachie, Akihiro; Varga, Zsuzsa; Vercellotti, Gregory M.; Eaton, John W.; Balla, György.

In: Blood, Vol. 100, No. 3, 01.08.2002, p. 879-887.

Research output: Contribution to journalArticle

Jeney, Viktória ; Balla, József ; Yachie, Akihiro ; Varga, Zsuzsa ; Vercellotti, Gregory M. ; Eaton, John W. ; Balla, György. / Pro-oxidant and cytotoxic effects of circulating heme. In: Blood. 2002 ; Vol. 100, No. 3. pp. 879-887.
@article{fa92db06c6b64ddc8badfc70c745f672,
title = "Pro-oxidant and cytotoxic effects of circulating heme",
abstract = "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.",
author = "Vikt{\'o}ria Jeney and J{\'o}zsef Balla and Akihiro Yachie and Zsuzsa Varga and Vercellotti, {Gregory M.} and Eaton, {John W.} and Gy{\"o}rgy Balla",
year = "2002",
month = "8",
day = "1",
doi = "10.1182/blood.V100.3.879",
language = "English",
volume = "100",
pages = "879--887",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "3",

}

TY - JOUR

T1 - Pro-oxidant and cytotoxic effects of circulating heme

AU - Jeney, Viktória

AU - Balla, József

AU - Yachie, Akihiro

AU - Varga, Zsuzsa

AU - Vercellotti, Gregory M.

AU - Eaton, John W.

AU - Balla, György

PY - 2002/8/1

Y1 - 2002/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0036682472&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036682472&partnerID=8YFLogxK

U2 - 10.1182/blood.V100.3.879

DO - 10.1182/blood.V100.3.879

M3 - Article

C2 - 12130498

AN - SCOPUS:0036682472

VL - 100

SP - 879

EP - 887

JO - Blood

JF - Blood

SN - 0006-4971

IS - 3

ER -