Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients

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Abstract

Background/Aims: Matrix metalloproteinases (MMPs), their inhibitors (TIMPs), oxidative stress (SOX) and kynurenine (KYN) pathway have been postulated in cardiovascular disease (CVD) progression. We hypothesized the possible association between the MMP/TIMP system, KYNs and CVD prevalence in continuous ambulatory peritoneal dialysis (CAPD) patients. Methods: We assessed MMP-2, MMP-9, TIMP-1, TIMP-2, KYN and its metabolite – quinolinic acid (QA), and SOX marker – Cu/Zn superoxide dismutase (Cu/Zn SOD) levels in CAPD patients both with and without CVD and healthy controls. Results: MMP-2, TIMP-2, Cu/Zn SOD, KYN and QA were significantly higher in CAPD patients with CVD than in patients without CVD and controls. MMP-2 and TIMP-2 were positively correlated with QA and Cu/Zn SOD levels, and the strong association was between MMP-2 and TIMP-2 levels. Multiple regression analyses identified Cu/Zn SOD, TIMP-2, QA and QA/KYN ratio as the factors independently associated with MMP-2, whereas MMP-2 and Cu/Zn SOD were independent variables affecting TIMP-2 levels. Conclusions: MMP-2 and TIMP-2 concentrations were higher in CAPD patients with CVD than in patients without CVD and healthy controls. Upregulation of the MMP-2/TIMP-2 system was associated with QA levels and increased oxidative status, suggesting the connection between KYN pathway activation, arterial remodeling and CVD prevalence in uremic patients on CAPD treatment.

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

Z. Galis, G Sukhova, 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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Endogenous kynurenines as targets for drug discovery and development.

Trevor W Stone, L Gail Darlington (2002)

The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.

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Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability.

S. Rajagopalan, S Ramasamy, Tyrone G. Harrison … (1996)

Vulnerable areas of atherosclerotic plaques often contain lipid-laden macrophages and display matrix metalloproteinase activity. We hypothesized that reactive oxygen species released by macrophage-derived foam cells could trigger activation of latent proforms of metalloproteinases in the vascular interstitium. We showed that in vivo generated macrophage foam cells produce superoxide, nitric oxide, and hydrogen peroxide after isolation from hypercholesterolemic rabbits. Effects of these reactive oxygens and that of peroxynitrite, likely to result from simultaneous production of nitric oxide and superoxide, were tested in vitro using metalloproteinases secreted by cultured human vascular smooth muscle cells. Enzymes in culture media or affinity-purified (pro-MMP-2 and MMP-9) were examined by SDS-PAGE zymography, Western blotting, and enzymatic assays. Under the conditions used, incubation with xanthine/xanthine oxidase increased the amount of active gelatinases, while nitric oxide donors had no noticeable effect. Incubation with peroxynitrite resulted in nitration of MMP-2 and endowed it with collagenolytic activity. Hydrogen peroxide treatment showed a catalase-reversible biphasic effect (gelatinase activation at concentrations of 4 microM, inhibition at > or = 10-50 microM). Thus, reactive oxygen species can modulate matrix degradation in areas of high oxidant stress and could therefore contribute to instability of atherosclerotic plaques.

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Author and article information

Journal

Journal ID (publisher-id): NEC

Journal ID (nlm-ta): Nephron Clin Pract

Journal ID (doi): 10.1159/issn.1660-2110

Title: Nephron Clinical Practice

Publisher: S. Karger AG

ISSN (Electronic): 1660-2110

Publication date Subscription-year: 2010

Publication date (Print): July 2010

Publication date (Electronic): 28 April 2010

Volume: 115

Issue: 4

Pages: c251-c258

Affiliations

Departments of ^aMonitored Pharmacotherapy, ^bCardiology, and ^cNephrology and Clinical Transplantation, Medical University, Bialystok, and ^dDepartment of Medical Science, University of Warmia and Mazury, Olsztyn, Poland

Article

Publisher ID: 313483 Other ID: Nephron Clin Pract 2010;115:c251–c258

DOI: 10.1159/000313483

PubMed ID: 20424475

SO-VID: c9bd78d4-ddef-4f65-abc4-d4d1b0a64b41

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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

Date received : 28 July 2009

Date accepted : 12 July 2009

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Figures: 2, Tables: 2, References: 29, Pages: 1

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Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients

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Abstract

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Karger: Nephrology

Most cited references 19

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

Endogenous kynurenines as targets for drug discovery and development.

Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability.

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