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      Effect of TGF-β 1 Antisense S-Oligonucleotide on Synthesis and Accumulation of Matrix Proteoglycans in Balloon Catheter-Injured Neointima of Rabbit Carotid Arteries

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          Abstract

          Arterial matrix proteoglycans (PG) are necessary for the maintenance of viscoelastic properties of the vessel wall, but excess levels, particularly of versican and biglycan in primary and restenotic intimal thickenings, are correlated with increased tissue volume and with atherogenicity. There is good evidence that the primary stimulus to increased PG synthesis, including versican and biglycan, is transforming growth factor-β<sub>1</sub> (TGF-β<sub>1</sub>). The aim of this study was to determine the effects of reducing endogenous TGF-β<sub>1</sub> on rates and patterns of PG synthesis and on versican, biglycan and decorin accumulation in vivo. Rabbit common carotid arteries subjected to balloon catheter injury were treated with a TGF-β<sub>1</sub> antisense phosphorothioate oligonucleotide applied in a pluronic gel to the adventitia. Control animals received a nonsense oligonucleotide or gel alone. TGF-β<sub>1</sub> antisense (1) significantly (p < 0.005) inhibited, at day 2, the balloon catheter-induced increase in TGF-β<sub>1</sub> mRNA relative to β-actin mRNA; (2) inhibited intimal thickening at 23 days by ∼40% (p < 0.05); (3) inhibited (p < 0.05) PG synthesis, measured by autoradiographic detection of [<sup>3</sup>H]glucosamine, in the media of day 2 ballooned carotids and in the subendothelial zone of day 23 neointima, and (4) decreased immunostaining intensity for versican (p < 0.03) and TGF-β<sub>1</sub> (p < 0.001) in the neointima. Biglycan was reduced to a lesser extent but not significantly and decorin was not affected. Proliferating cell nuclear antigen indices were variable and not significantly changed. These findings confirm a role for TGF-β<sub>1</sub> in developing neointima and demonstrate a specific effect on the synthesis, distribution, and accumulation of matrix PG, particularly versican.

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          Most cited references 5

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          Transforming growth factor beta in tissue fibrosis.

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            Phosphorothioate oligodeoxynucleotides bind to basic fibroblast growth factor, inhibit its binding to cell surface receptors, and remove it from low affinity binding sites on extracellular matrix.

            We studied the interactions of phosphorothioate oligodeoxynucleotides and heparin-binding growth factors. By means of a gel mobility shift assay, we demonstrated that phosphodiester and phosphorothioate homopolymers bound to basic fibroblast growth factor (bFGF). Binding of a probe phosphodiester oligodeoxynucleotide could also be shown for other proteins of the FGF family, including acidic fibroblast growth factor (aFGF), Kaposi's growth factor (FGF-4) as well as for the bFGF-related vascular endothelial growth factor, VEGF. No binding to epidermal growth factor (EGF) was observed. In addition, using a radioreceptor assay, we have shown that phosphorothioate homopolymers of cytidine and thymidine blocked binding of not only 125I-bFGF, but also of 125I-PDGF to NIH 3T3 cells, whereas phosphodiester oligodeoxynucleotides were ineffective. The extent of blockade of binding was dependent on the chain length of the phosphorothioate oligodeoxynucleotide. Furthermore, we have examined the effects of 18-mer phosphorothioate oligodeoxynucleotides of different sequences on 125I-bFGF binding to low and high affinity sites on both NIH 3T3 fibroblasts and DU-145 prostate cancer cells. Despite the fact that we have observed inhibition of bFGF binding by the 18-mer phosphorothioate oligodeoxynucleotides for both the high and low affinity classes of bFGF receptor, the inhibition was sequence-selective only for the high affinity receptors. We have also demonstrated that phosphorothioate homopolymers of cytidine and thymidine release bFGF bound to low affinity receptors in extracellular matrix (ECM). Finally, the most potent phosphorothioate oligodeoxynucleotides used in these experiments (e.g. SdC28) were inhibitors of bFGF-induced DNA synthesis in NIH 3T3 cells.
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              Mechanical loading and TGF-beta regulate proteoglycan synthesis in tendon.

              Fibrocartilage is found in tendon at sites where the tissue is subjected to transverse compressive loading in vivo. A significant characteristic of the tissue transition from tendon to fibrocartilage in bovine deep flexor tendon is increased gene expression, synthesis, and accumulation of both a large proteoglycan, aggrecan, and a small proteoglyoan, biglycan. In order to investigate the cellular events involved in this response, segments of fetal bovine deep flexor tendon were subjected in vitro to cyclic compressive load for 72 h. Following loading, the level of aggrecan mRNA in cells from loaded tissue was increased 200-450% compared to matched nonloaded tissue segments, as determined by slot-blot analysis. The level of biglycan mRNA increased 100%, and the level of versican mRNA increased 130% in the loaded tissue. The level of decorin mRNA remained virtually unchanged, while expression of alpha 1(I) collagen increased only 40%. When tissue segments were cultured in the presence of transforming growth factor (TGF)-beta 1 (1 ng/ml), the synthesis and expression of mRNA for both aggrecan and biglycan increased, whereas decorin expression was not affected. Similarity in both the direction and the pattern of the cellular response to mechanical load and TGF-beta suggested a causal relationship. Both loading of tendon segments and TGF-beta treatment increased expression of mRNA for TGF-beta by approximately 40% compared to control tissue. In addition, the amount of newly synthesized TGF-beta immunoprecipitated from extracts of loaded tissue was several-fold greater than that from nonloaded tissue. The experiments of this study support a hypothesis suggesting that one aspect of the response of cells in fetal tendon to compressive load is increased TGF-beta synthesis which, in turn, stimulates synthesis of extracellular matrix proteoglycans and leads toward fibrocartilage formation.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2000
                February 2000
                07 March 2000
                : 37
                : 1
                : 50-60
                Affiliations
                aDepartment of Anatomy, School of Medicine, The University of Auckland, Auckland, New Zealand, and bDepartment of Anatomical Sciences, University of Queensland, Brisbane, Australia
                Article
                25713 J Vasc Res 2000;37:50–60
                10.1159/000025713
                10720886
                © 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: 7, Tables: 1, References: 40, Pages: 11
                Categories
                Research Paper

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