Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress.
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.
Asatryan
Liana
L
University of Southern California, School of Pharmacy, Department of Molecular Pharmacology and Toxicology, 1985 Zonal Ave, PSC 622, Los Angeles, CA 90089, USA.
Ziouzenkova
Ouliana
O
Duncan
Roger
R
Sevanian
Alex
A
D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000166:cytology; D001161:Arteriosclerosis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006454:Hemoglobins / Q000493:pharmacokinetics*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000493:pharmacokinetics*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010545:Peroxides / Q000494:pharmacology*; D011817:Rabbits
D006454:Hemoglobins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D010545:Peroxides; D006418:Heme; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1