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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-01-0293. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-01-0293v1 102/5/1732    most recent 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 Asatryan, L. Articles by Sevanian, A. Search for Related Content PubMed PubMed Citation Articles by Asatryan, L. Articles by Sevanian, A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2003, Vol. 102, No. 5, pp. 1732-1739 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress Liana Asatryan, Ouliana Ziouzenkova, Roger Duncan, and Alex Sevanian From the Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles; and Department of Vascular Medicine, Brigham and Women's Hospital, Harvard University, Boston, MA. Low-density lipoprotein (LDL) oxidation mediated by a variety of catalysts in atherosclerotic lesions plays a crucial role in the genesis and evolution of atherosclerotic plaques. In this study we focused on oxidative properties of hemoglobin (Hb)–modified LDL because Hb is present in atherosclerotic lesions. Under low oxygen tensions Hb was previously found to modify apolipoprotein B100 with covalent binding of Hb fragments and formation of electronegative LDL particles (LDL–). Here we show that HbLDL is highly susceptible to oxidation, but is not cytotoxic to vascular cells, as was found for LDL– isolated from human plasma. HbLDL and LDL– have similar levels of oxidized lipid products and low uptake rates; however, the virtual absence of HbLDL-induced toxicity depends on a marked adaptive oxidative stress response. This was evidenced by a time- and dose-dependent induction of heme oxygenase (HO-1). Cell survival was significantly decreased in the presence of HO-1 inhibitor, tin protoporphyrin (SnPPIX). HO-1 induction by HbLDL increased resistance of cells to toxic doses of hemin or t-BuOOH. The high sensitivity to oxidation and HO-1 induction was largely dependent on lipid hydroperoxides and heme associated with HbLDL. Reduction of pre-existing lipid peroxides using ebselen delayed HbLDL kinetics and inhibited HO-1 induction. Moreover, heme inactivation or its degradation inhibited HO-1 induction and provided an additive inhibitory effect to ebselen. We conclude that Hb-catalyzed reactions may modulate vascular cell survival and oxidative stress adaptation due to the presence of peroxides and heme, thus providing a possible mechanism for the evolution of atherosclerotic and hemorrhagic lesions. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: I. S. Naarmann, C. Harnisch, N. Flach, E. Kremmer, H. Kuhn, D. H. Ostareck, and A. Ostareck-Lederer mRNA Silencing in Human Erythroid Cell Maturation: HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN K CONTROLS THE EXPRESSION OF ITS REGULATOR c-Src J. Biol. Chem., June 27, 2008; 283(26): 18461 - 18472. [Abstract] [Full Text] [PDF]

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