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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Jeney, V. Articles by Balla, G. Search for Related Content PubMed PubMed Citation Articles by Jeney, V. Articles by Balla, G. Related Collections Hemostasis, Thrombosis, and Vascular Biology Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 August 2002, Vol. 100, No. 3, pp. 879-887 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Pro-oxidant and cytotoxic effects of circulating heme Viktória Jeney, József Balla, Akihiro Yachie, Zsuzsa Varga, Gregory M. Vercellotti, John W. Eaton, and György Balla From the Departments of Medicine and Neonatology, University of Debrecen, Hungary; Department of Laboratory Sciences, Kanazawa University, Japan; Department of Medicine, University of Minnesota, Minneapolis; and the James Graham Brown Cancer Center, University of Louisville, KY. 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 defenseHO-1 and ferritinis induced. These results may be relevant to a variety of disorderssuch as renal failure associated with intravascular hemolysis, hemorrhagic injury to the central nervous system, and, perhaps, atherogenesisin which hemoglobin-derived heme may promote the formation of fatty acid hydroperoxides. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Jadhav and J. F. Ndisang Heme Arginate Suppresses Cardiac Lesions and Hypertrophy in Deoxycorticosterone Acetate-Salt Hypertension Experimental Biology and Medicine, July 1, 2009; 234(7): 764 - 778. [Abstract] [Full Text] [PDF] K. Yunoki, T. Naruko, R. Komatsu, S. Ehara, N. Shirai, K. Sugioka, M. Nakagawa, C. Kitabayashi, Y. Ikura, A. Itoh, et al. Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes Eur. Heart J., June 25, 2009; (2009) ehp257v1. 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