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


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          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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          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.

                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                03 August 2000
                : 18
                : 3
                : 169-176
                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
                14415 Blood Purif 2000;18:169–176
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 2, References: 50, Pages: 8
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/14415
                Self URI (text/html): https://www.karger.com/Article/FullText/14415
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology

                Cardiovascular Medicine,Nephrology
                Electronegative LDL,Dense LDL,Hemoglobin,Radical,Lipid peroxidation,Vitamin E,Vitamin C,Dityrosines,Apolipoprotein B-100,Hemodialysis,Diabetes


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