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      Serum Starvation and Growth Factor Receptor Expression in Vascular Smooth Muscle Cells

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          Abstract

          Background: Smooth muscle cell (SMC) proliferation in atherosclerosis is regulated through the interaction of growth factors like platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor-1 (IGF-1) and their receptors (R). We hypothesized that serum starvation of SMCs may affect PDGFβ-R and IGF-1-R expression and, consequently, the effect of their cognate ligands on SMC survival/proliferation. Methods and Results: Serum starvation significantly increases PDGFβ-R but not IGF-1-R mRNA and protein expression in SMCs. PDGF-BB stimulates cell survival but not proliferation in serum-starved SMCs of the synthetic phenotype, whereas SMCs of the contractile phenotype respond to PDGF-BB by a significant increase in proliferation. Immunohistochemical analysis of coronary atherosclerotic lesions reveals PDGFβ-R expression in SMCs in the lamina fibromuscularis, but not in the media and in healthy parts of the arterial wall. No such differential expression was observed for IGF-1-R. Conclusions: Differential regulation of PDGFβ-R and IGF-1-R expression by serum starvation might represent a mechanism for the control of SMC survival/proliferation in atherogenesis and restenosis. The distribution of PDGFβ-Rs and IGF-1-Rs in atherosclerotic lesions may indicate an effect of serum starvation on SMCs in the arterial wall.

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          Most cited references 13

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          High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

          Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability.
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            Intracellular protein catabolism and its control during nutrient deprivation and supply.

             E Mortimore,  A Pösö (1986)
            The continuous turnover of intracellular protein and other macromolecules is a basic cellular process that serves, among other functions, to regulate cytoplasmic content and provide amino acids for ongoing oxidative and biosynthetic reactions during nutrient deprivation. The intensity of breakdown and pattern of regulation, though, vary widely among cells. Rat hepatocytes, for example, exhibit high absolute rates of proteolysis and regulatory effects that diminish during starvation, while corresponding responses in skeletal and cardiac muscle move in the opposite direction. It is also becoming apparent that effects of insulin and other acute regulatory agents on muscle breakdown are limited to nonmyofibrillar components. The latter may be sequestered and degraded within autophagic vacuoles, whereas myofibrillar proteins require an initial attack by calcium-dependent proteases in the cytosol. By contrast, most if not all of the breakdown of resident (long-lived) proteins as well as RNA in the hepatocyte can be explained by lysosomal mechanisms. The uptake of cytoplasmic components by lysosomes can be divided into two major categories, macroautophagy and micro- or basal autophagy. The first is induced by amino acid or insulin/serum deprivation. In the hepatocyte, amino acids alone can regulate this process almost instantaneously over two thirds of the full range of proteolysis, 4.5% to 1.5% per hour. Glucagon, cyclic AMP, and beta-agonists also stimulate macroautophagy in hepatocytes but have opposite effects in skeletal and cardiac myocytes. Basal autophagy differs from the macro type in that the cytoplasmic "bite" is smaller and sequestration is not acutely regulated. It is, however, adaptively decreased during starvation in parallel with absolute rates of basal turnover. Since endoplasmic reticulum comprises an appreciable fraction of the vacuolar content, volume sequestration would be compatible with the known heterogeneity of individual protein turnover if some proteins (or altered proteins) selectively bind to membranes. The amino acid control of macroautophagy in the hepatocyte is accomplished by a small group of direct inhibitors (Leu, Tyr/Phe, Gln, Pro, Met, Trp, and His) and the permissive effect of alanine whereas only leucine is involved in myocytes and adipocytes. Of unusual interest is the fact that the inhibitory amino acid group alone evokes responses in perfused livers that are identical to those of a complete plasma mixture at 0.5 and 4 times normal plasma levels but loses effectiveness almost completely at normal concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
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              PDGF ligand and receptor gene expression during repair of arterial injury

              Smooth muscle cells (SMC) in rat carotid artery leave the quiescent state and proliferate after balloon catheter injury, but the signals for mitogenesis are not known. In this study, the possibility that cells within damaged arteries produce a growth factor that could act locally to stimulate SMC replication and repair was examined. We found that the genes for PDGF-A and -B (ligand) and PDGF receptor (alpha and beta subunits) were expressed in normal and injured carotid arteries and were independently regulated during repair of carotid injury. Two phases of PDGF ligand and receptor gene expression were observed: (a) In the early stage, a large decrease in PDGF beta-receptor mRNA levels preceded 10- to 12-fold increases in PDGF-A transcript abundance in the first 6 h after wounding. No change in PDGF alpha-receptor or PDGF-B gene expression was found at these times. (b) In the chronic phase, 2 wk after injury, neointimal tissue had lower levels of PDGF alpha- receptor mRNA (threefold) and higher levels of PDGF beta-receptor mRNA (three- to fivefold) than did restored media. Moreover, in situ hybridization studies identified a subpopulation of neointimal SMC localized at or near the luminal surface with a different pattern of gene expression than the underlying carotid SMC. Luminal SMC were strongly positive for PDGF-A and PDGF beta-receptor transcripts, while showing little or no hybridization for PDGF-B or PDGF alpha-receptor. Immunohistochemical studies showed strongly positive staining for PDGF- A in SMC along the luminal surface. These data show that changes in PDGF ligand and receptor expression occur at specific times and locations in injured carotid artery and suggest that these changes may play a role in regulating arterial wound repair.
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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
                2006
                February 2006
                16 February 2006
                : 43
                : 2
                : 157-165
                Affiliations
                aCenter for Cell and Gene Therapy, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex., USA; bInstitute of Clinical Chemistry and Laboratory Medicine, University of Mainz, Mainz, and cDepartment of Internal Medicine II-Cardiology, and dDepartment of Cardiac Surgery, University of Ulm, Ulm, Germany
                Article
                90945 J Vasc Res 2006;43:157–165
                10.1159/000090945
                16407661
                © 2006 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: 6, References: 37, Pages: 9
                Categories
                Research Paper

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