title: Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment.
abstract: Iron-derived reactive oxygen species are involved in the pathogenesis of numerous vascular disorders. One abundant source of redox active iron is heme, which is inherently dangerous when it escapes from its physiologic sites. Here, we present a review of the nature of heme-mediated cytotoxicity and of the strategies by which endothelium manages to protect itself from this clear and present danger. Of all sites in the body, the endothelium may be at greatest risk of exposure to heme. Heme greatly potentiates endothelial cell killing mediated by leukocytes and other sources of reactive oxygen. Heme also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. Hemoglobin in plasma, when oxidized, transfers heme to endothelium and lipoprotein, thereby enhancing susceptibility to oxidant-mediated injury. As a defense against such stress, endothelial cells upregulate heme oxygenase-1 and ferritin. Heme oxygenase opens the porphyrin ring, producing biliverdin, carbon monoxide, and a most dangerous product-redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of heme and oxidants; lack of adaptation in an iron-rich environment led to extensive endothelial damage in humans.
authors.affiliation: Department of Medicine, University of Debrecen, Debrecen, Hungary. balla@internal.med.unideb.hu
authors.forename: József
authors.initials: J
authors.lastname: Balla
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
authors.forename: Viktória
authors.initials: V
authors.lastname: Jeney
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Varga
authors.forename: Harry S
authors.initials: HS
authors.lastname: Jacob
authors.forename: John W
authors.initials: JW
authors.lastname: Eaton
authors.forename: György
authors.initials: G
authors.lastname: Balla
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology; D005293:Ferritins / Q000378:metabolism / Q000494:pharmacology; D006418:Heme / Q000378:metabolism / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000737:chemistry; D008954:Models, Biological; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D006454:Hemoglobins; D008077:Lipoproteins, LDL; D016877:Oxidants; D006418:Heme; D005293:Ferritins; D051547:Heme Oxygenase-1