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      Oxidative Modification of Low-Density Lipoprotein (LDL) in HD Patients: Role in Electronegative LDL Formation

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          Abstract

          High cardiovascular mortality in patients on hemodialysis (HD) is largely attributed to oxidative stress and altered lipoprotein profiles. Markedly increased levels of mildly modified LDL subfractions, such as dense LDL and electronegatively charged LDL (LDL<sup>–</sup>), are present in the blood of HD patients and may be markers of atherosclerosis risk. LDL<sup>–</sup>, characterized by modified protein content and elevated levels of lipid peroxidation products, is representative of multiple oxidative processes acting on plasma lipoproteins that prevail during HD. In this review, we discussed known mechanisms leading to that may account for oxidative protein modification and/or LDL<sup>–</sup> formation in the context of specific conditions associated with HD.

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          Most cited references 11

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          The role of oxidized lipoproteins in atherogenesis

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            The role of lipid peroxidation and antioxidants in oxidative modification of LDL

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              Mass spectrometric quantification of markers for protein oxidation by tyrosyl radical, copper, and hydroxyl radical in low density lipoprotein isolated from human atherosclerotic plaques.

              Lipoprotein oxidation has been implicated in the pathogenesis of atherosclerosis. However, the physiologically relevant pathways mediating oxidative damage have not yet been identified. Three potential mechanisms are tyrosyl radical, hydroxyl radical, and redox active metal ions. Tyrosyl radical forms o,o'-dityrosine cross-links in proteins. The highly reactive hydroxyl radical oxidizes phenylalanine residues to o-tyrosine and m-tyrosine. Metal ions oxidize low density lipoprotein (LDL) by poorly understood pathways. To explore the involvement of tyrosyl radical, hydroxyl radical, and metal ions in atherosclerosis, we developed a highly sensitive and quantitative method for measuring levels of o, o'-dityrosine, o-tyrosine, and m-tyrosine in proteins, lipoproteins, and tissue, using stable isotope dilution gas chromatography-mass spectrometry. We showed that o,o'-dityrosine was selectively produced in LDL oxidized with tyrosyl radical. Both o-tyrosine and o, o'-dityrosine were major products when LDL was oxidized with hydroxyl radical. Only o-tyrosine was formed in LDL oxidized with copper. Similar profiles of oxidation products were observed in bovine serum albumin oxidized with the three different systems. Applying these findings to LDL isolated from human atherosclerotic lesions, we detected a 100-fold increase in o,o'-dityrosine levels compared to those in circulating LDL. In striking contrast, levels of o-tyrosine and m-tyrosine were not elevated in LDL isolated from atherosclerotic tissue. Analysis of fatty streaks revealed a similar pattern of oxidation products; compared with normal aortic tissue, there was a selective increase in o,o'-dityrosine with no change in o-tyrosine. The detection of a selective increase of o,o'-dityrosine in LDL isolated from vascular lesions is consistent with the hypothesis that oxidative damage in human atherosclerosis is mediated in part by tyrosyl radical. In contrast, these observations do not support a role for free metal ions as catalysts of LDL oxidation in the artery wall.
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                978-3-8055-7083-1
                978-3-318-00584-4
                0253-5068
                1421-9735
                2000
                2000
                03 August 2000
                : 18
                : 3
                : 169-176
                Affiliations
                aVascular Medicine and Atherosclerosis Unit, Brigham and Women’s Hospital, Harvard University, Boston, Mass. and bDepartment of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, Calif., USA
                Article
                14415 Blood Purif 2000;18:169–176
                10.1159/000014415
                10859419
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 2, References: 50, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/14415
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