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      Oxysterols Are Increased in Plasma of End-Stage Renal Disease Patients

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          Abstract

          Background/Aims: Oxidative stress occurs in chronic renal failure patients undergoing hemodialysis (HD). The objective of our study was to measure oxidation products of cholesterols, so-called oxysterols, in the serum of HD patients in comparison to healthy control persons. Methods: In 42 HD patients, plasma oxysterols were measured before and after HD. The values were compared with those in 40 healthy controls. The following cholesterol derivatives were analyzed: dienes, 7β-OH, β-epoxy, α-epoxy, 20α-OH, α-triol, and 7-keto cholesterol. Results: In HD patients, serum levels of oxysterols are increased in comparison to controls. The highest values were measured for β-epoxy cholesterol and for 20α-OH cholesterol. During HD oxysterol concentrations increased, obviously by water removal and concentration of nondialyzable compounds. Conclusion: Due to oxidative stress which is known as a typical sign of chronic renal failure the plasma concentrations of oxysterols are also significantly increased in comparison to healthy controls. This underlines the data on accelerated lipid peroxidation in end-stage renal disease (ESRD) patients. Accumulated oxysterols which are accused of exerting atherosclerosis-stimulating effects, which can contribute to the increased cardiovascular risk of ESRD patients, could either induce atherosclerosis via signaling or chronic effects. Direct chemical reactions stimulating plaque formation can be excluded because of the low levels of oxysterols. The share of oxysterols within the total cholesterol ranges from 4 to 15‰.

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          NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells.

          The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca(2+) oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH(2)-terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.
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            Oxysterols and atherosclerosis

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              7-ketocholesterol induces protein ubiquitination, myelin figure formation, and light chain 3 processing in vascular smooth muscle cells.

              Oxysterols such as 7-ketocholesterol (7-KC) are important mediators of cell death in atherosclerosis. Therefore, in vitro studies of human smooth muscle cell (SMC) death in response to 7-KC were undertaken to investigate the potential mechanisms. Human aortic SMCs treated with 7-KC showed enhanced immunoreactivity for the oxidative stress marker 4-hydroxy-2-nonenal and upregulated several stress genes (70-kDa heat shock protein 1, heme oxygenase 1, and growth arrest and DNA damage-inducible protein 153) at the mRNA but not at the protein level. 7-KC-treated SMCs rapidly underwent cell death as determined by neutral red, counting of adherent cells, and depolarization of the mitochondrial inner membrane. Cell death was associated with upregulation of ubiquitin mRNA and ubiquitination of cellular proteins. Inhibition of the proteasome by lactacystin potentiated considerably the toxicity of 7-KC. Transmission electron microscopy revealed formation of myelin figures, extensive vacuolization, and depletion of organelles. Formation of autophagosomes was suggested by labeling cells with LysoTracker and monitoring processing of microtubule-associated protein 1 light chain 3 (LC3). Analogous to our in vitro studies, human atherosclerotic plaques showed signs of ubiquitination in SMCs. 7-KC activates the ubiquitin-proteasome system and induces a complex mode of cell death associated with myelin figure formation and processing of LC3 evocating autophagic processes.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                978-3-8055-8058-8
                978-3-318-01305-4
                1420-4096
                1423-0143
                2005
                March 2006
                20 March 2006
                : 28
                : 5-6
                : 302-306
                Affiliations
                aResearch Institute of Physiotherapy and Gerontology, KortexMed Institute of Medical Education, Bad Harzburg, and bDepartment of Pathobiochemistry, Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University, Magdeburg, Germany; cDepartment of Nephrology AUSL-LE2, Scorrano/Lecce, Italy; dInstitute of Environmental Medicine at Heinrich Heine University, Düsseldorf, Germany; eDepartment of Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, Calif., USA; fDepartment of Nephrology and Medical Intensive Care, Charité University Clinic, Berlin, Germany; gEuropean Group of Clinical Research on Oxidative Stress
                Article
                91133 Kidney Blood Press Res 2005;28:302–306
                10.1159/000091133
                16534225
                f7bc05ea-91c2-431e-90c0-1d6589b3a2ea
                © 2005 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.

                History
                Page count
                Figures: 3, References: 19, Pages: 5
                Categories
                Managing Coronary Heart Disease in Chronic Uremia

                Cardiovascular Medicine,Nephrology
                Atherosclerosis,Oxidative stress,Hemodialysis,End-stage renal disease,Lipid peroxidation,Oxysterols,Chronic renal failure

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