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      Long-Term Erythropoietin Therapy Does Not Affect Metalloproteinases and Their Inhibitor Levels, Oxidative Stress and Inflammation in Hemodialyzed Patients

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          Abstract

          Background: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in the atherosclerosis. Recombinant human erythropoietin (EPO) has become widely used to treat anemic hemodialyzed (HD) patients; however, an increased mortality has been reported for HD patients with cardiovascular disease when randomly assigned to normal hematocrit by EPO. Therefore, we conducted a study examining the effect of EPO on MMPs/TIMPs system, oxidative stress and inflammation in these patients. Methods: Assessment of MMP-2, MMP-9, TIMP-1 and TIMP-2 were performed in 20 stable HD patients and 15 healthy controls. Additionally, the effects of EPO on malondialdehyde (MDA) – a marker of SOX and C-reactive protein (CRP) levels – as a marker of inflammation were also investigated. Of the 20 patients, 10 were receiving EPO therapy [HD-EPO(+)] for 12 months or more and 10 were not receiving EPO therapy [HD-EPO(–)]. Both groups were not receiving iron supplementation. Results: All parameters, with the exception of MMP-9, were lower in the healthy subjects compared with the HD subjects, irrespective of EPO administration. There was no difference in MMPs/TIMPs system, MDA and C-reactive levels between HD-EPO(+) and HD-EPO(–) patients. Conclusion:Erythropoietin therapy did not influence MMPs/TIMPs system, inflammation, or SOX in a low-risk HD patient population, in the absence of concomitant iron supplementation and mean Hg levels within target.

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          Most cited references 15

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          Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques.

           Z Galis,  P. Libby,  M Lark (1994)
          Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We investigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM components in human atherosclerotic plaques (n = 30) and in uninvolved arterial specimens (n = 11). We studied members of all three MMP classes (interstitial collagenase, MMP-1; gelatinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immunocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts contained activated forms of gelatinases determined zymographically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active matrix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymography revealed gelatinolytic and caseinolytic activity in frozen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvasculature of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic intervention.
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            Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease.

            Matrix metalloproteinase (MMP)-9 secretion by macrophages and other inflammatory cells accelerates atherosclerotic progression and destabilizes vulnerable plaque in animal models. However, epidemiological data evaluating the prognostic impact of circulating concentrations and functional genetic variations of MMP-9 are lacking. In a prospective study of 1127 patients with documented coronary artery disease, we measured baseline plasma MMP-9 levels and determined the MMP-9/C-1562T and MMP-9/R279Q genotypes. During the follow-up period (mean of 4.1 years), 97 patients died from cardiovascular (CV) causes. Median concentrations of MMP-9 were significantly higher among patients who experienced a fatal CV event than among those who did not (62.2 versus 47.8 ng/mL; P<0.0001). The crude hazard risk ratio of CV death associated with increasing quartiles of MMP-9 was 1.4 (95% CI, 1.2 to 1.8; P<0.0001), and after adjustment for clinical and therapeutic confounders, it was 1.3 (95% CI, 1.1 to 1.6; P=0.005). Additional adjustment for highly sensitive CRP, interleukin-6, fibrinogen, and interleukin-18 revealed a hazard risk ratio to 1.2 (95% CI, 0.9 to 1.6; P=0.15). The T allele of the C-1562T polymorphism was associated with increased MMP-9 levels in a fairly codominant fashion (P=0.004). Although none of the polymorphisms was significantly related with future CV death, there was a significant association (P=0.02) between the R279Q polymorphism and CV events in patients with stable angina. Plasma MMP-9 concentration was identified as a novel predictor of CV mortality in patients with coronary artery disease. Whether it provides independent prognostic information compared with other inflammatory markers will have to be additionally assessed.
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              Clinical and echocardiographic disease in patients starting end-stage renal disease therapy

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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2007
                May 2007
                23 March 2007
                : 27
                : 3
                : 221-225
                Affiliations
                aDepartment of Nephrology and Clinical Transplantation and bPharmacodynamics, Medical University, Bialystok, Poland
                Article
                101191 Am J Nephrol 2007;27:221–225
                10.1159/000101191
                17384500
                © 2007 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
                Tables: 2, References: 20, Pages: 5
                Categories
                Original Report: Patient-Oriented, Translational Research

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