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      Parathyroid Hormone Has a Prosclerotic Effect on Vascular Smooth Muscle Cells

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          Abstract

          Although accelerated atherosclerosis and arteriosclerosis are common in patients with renal failure, the pathogenesis of these changes is poorly understood. Parathyroid hormone (PTH) levels are elevated in renal failure, and have been linked to uraemic vascular changes in some studies. We examined the in vitro effects of increasing doses of the 1–34 fragment of PTH on human aortic vascular smooth muscle cells (VSMCs). Factors examined were: (1) collagen production using tritiated hydroxyproline incorporation and transcription of procollagen α<sub>1</sub>(I) mRNA; (2) change in the surface area of collagen I lattices; (3) mRNA transcription of the collagen binding protein β1 integrin; (4) proliferation using tritiated thymidine incorporation, and (5) methyl tetrazolium salt conversion to estimate live cell number after 5 days’ exposure to PTH. PTH at a concentration of 200 pmol/l increased total collagen synthesis (188 ± 25% of control, p < 0.01) as well as transcription of procollagen α<sub>1</sub>(I) mRNA (136 ± 11% of control, p < 0.005). PTH also increased reorganisation of collagen I lattices (surface area 47 ± 8% of well for control vs. 35.7 ± 2.5 and 34.3 ± 3.0% for PTH 100 and 200 pmol/l, respectively, p = 0.02) and upregulated β1 integrin mRNA expression (160 ± 20% of control at PTH concentration of 200 pmol/l, p < 0.05). PTH had no effect on VSMC proliferation or number at doses up to 200 pmol/l. In conclusion, PTH increases production and reorganisation of collagen by VSMCs in vitro. It is possible that more aggressive control of hyperparathyroidism in patients with renal failure may help to reduce the burden of cardiovascular disease in this patient population.

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          Most cited references 9

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          Arterial calcification and pathology in uremic patients undergoing dialysis.

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            Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: a critical role for nuclear targeting.

            Parathyroid hormone-related protein (PTHrP) is a prohormone that is posttranslationally processed to a family of mature secretory forms, each of which has its own cognate receptor(s) on the cell surface that mediate the actions of PTHrP. In addition to being secreted via the classical secretory pathway and interacting with cell surface receptors in a paracrine/autocrine fashion, PTHrP appears to be able to enter the nucleus directly following translation and influence cellular events in an "intracrine" fashion. In this report, we demonstrate that PTHrP can be targeted to the nucleus in vascular smooth muscle cells, that this nuclear targeting is associated with a striking increase in mitogenesis, that this nuclear effect on proliferation is the diametric opposite of the effects of PTHrP resulting from interaction with cell surface receptors on vascular smooth muscle cells, and that the regions of the PTHrP sequence responsible for this nuclear targeting represent a classical bipartite nuclear localization signal. This report describes the activation of the cell cycle in association with nuclear localization of PTHrP in any cell type. These findings have important implications for the normal physiology of PTHrP in the many tissues which produce it, and suggest that gene delivery of PTHrP or modified variants may be useful in the management of atherosclerotic vascular disease.
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              Changes of vascular architecture independent of blood pressure in experimental uremia.

              Striking alterations of the structure of arterial vessels of different caliber are a well-known feature of renal failure, but it is currently unknown to what extent they are a reflection of hypertension or of uremia per se. To address this issue further we studied subtotally nephrectomized rats, sham-operated and pair-fed with matched controls. After uremia of 14 days' duration, stereologic measurements were carried out on perfusion-fixed tissue. To eliminate a potential influence of hypertension, subgroups of animals received furosemide and hydralazine in the drinking fluid to yield daily doses of 15 mg/kg and 20 mg/kg, respectively. At the end of the experiment, systolic blood pressure (tail plethysmography) was 110 +/- 13.3 (mean +/- SD) mm Hg and 99.4 +/- 8.1 mm Hg in untreated and treated controls, respectively, and 132 +/- 20.7 mm Hg and 103 +/- 13.0 mm Hg in untreated and treated uremic animals, respectively (n = 5 to 10 animals per group). The wall:lumen ratio of intramyocardial small arteries was 0.056 +/- 0.011 and 0.052 +/- 0.006 in untreated and treated controls, respectively. In untreated and treated uremic animals, the corresponding values were 0.077 +/- 0.011 and 0.066 +/- 0.007 (P < .01; control v uremia, ANOVA). A similar increase, unaffected by blood pressure treatment, was found for wall thickness of intramyocardial arteries. Analogous changes were also noted in mesenteric arterioles and veins. Finally, aorta media thickness was significantly (P < .005) higher in uremic animals than in controls (138 +/- 29 micrometers v 103 +/- micrometers).(ABSTRACT TRUNCATED AT 250 WORDS)
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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
                1420-4096
                1423-0143
                2003
                2003
                24 April 2003
                : 26
                : 1
                : 27-33
                Affiliations
                aDepartment of Nephrology and bDepartment of Medicine, University of Melbourne, The Royal Melbourne Hospital, Melbourne, Australia
                Article
                69761 Kidney Blood Press Res 2003;26:27–33
                10.1159/000069761
                12697974
                © 2003 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: 40, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/69761
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                Original Paper

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