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      Small Artery Remodeling and Erythrocyte Deformability in L-NAME-Induced Hypertension: Role of Transglutaminases

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          Abstract

          Background: Hypertension is associated with inward remodeling of small arteries and decreased erythrocyte deformability, both impairing proper tissue perfusion. We hypothesized that these alterations depend on transglutaminases, cross-linking enzymes present in the vascular wall, monocytes/macrophages and erythrocytes. Methods and Results: Wild-type (WT) mice and tissue-type transglutaminase (tTG) knockout (KO) mice received the nitric oxide inhibitor Nω-nitro- L-arginine methyl ester hydrochloride ( L-NAME) to induce hypertension. After 1 week, mesenteric arteries from hypertensive WT mice showed a smaller lumen diameter (–6.9 ± 2.0%, p = 0.024) and a larger wall-to-lumen ratio (11.8 ± 3.5%, p = 0.012) than controls, whereas inward remodeling was absent in hypertensive tTG KO mice. After 3 weeks, the wall-to-lumen ratio was increased in WT (20.8 ± 4.8%, p = 0.005) but less so in tTG KO mice (11.7 ± 4.6%, p = 0.026), and wall stress was normalized in WT but not in tTG KO mice. L-NAME did not influence expression of tTG or an alternative transglutaminase, coagulation factor XIII (FXIII). Suppression of FXIII by macrophage depletion was associated with increased tTG in the presence of L-NAME. L-NAME treatment decreased erythrocyte deformability in the WT mice (–15.3% at 30 dynes/cm<sup>2</sup>, p = 0.014) but not in the tTG KO mice. Conclusion: Transglutaminases are involved in small artery inward remodeling and erythrocyte stiffening associated with nitric oxide inhibition-related hypertension.

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          Most cited references 24

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          Transglutaminases: crosslinking enzymes with pleiotropic functions.

          Blood coagulation, skin-barrier formation, hardening of the fertilization envelope, extracellular-matrix assembly and other important biological processes are dependent on the rapid generation of covalent crosslinks between proteins. These reactions--which are catalysed by transglutaminases--endow the resulting supramolecular structure with extra rigidity and resistance against proteolytic degradation. Some transglutaminases function as molecular switches in cytoskeletal scaffolding and modulate protein-protein interactions. Having knowledge of these enzymes is essential for understanding the aetiologies of diverse hereditary diseases of the blood and skin, and various autoimmune, inflammatory and degenerative conditions.
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            Red cell deformability and its relevance to blood flow.

             S Chien (1986)
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              Prognostic significance of small-artery structure in hypertension.

              The presence of structural alterations in the microcirculation may be considered an important mechanism of organ damage; however, it is not currently known whether structural alterations of small arteries may predict fatal and nonfatal cardiovascular events. One hundred twenty-eight patients were included in the present study. There were 59 patients with essential hypertension, 17 with pheochromocytoma, 20 with primary aldosteronism, 12 with renovascular hypertension, and 20 normotensive patients with non-insulin-dependent diabetes mellitus. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media-to-internal lumen ratio (M/L) was measured. The subjects were reevaluated after an average follow-up time of 5.4 years. Thirty-seven subjects had a documented fatal or nonfatal cardiovascular event (5.32 events/100 patients per year). In the subcutaneous small arteries of subjects with cardiovascular events, a smaller internal diameter and a clearly greater M/L was observed. Our subjects were subdivided according to the presence of an M/L greater or smaller than the mean and median values observed in the whole population (0.098) or mean value +2 SD of our normal subjects (0.11). Life-table analyses showed a significant difference in event-free survival between the subgroups. Cox's proportional hazard model, considering all known cardiovascular risk factors, indicated that only pulse pressure (P=0.009) and M/L (P<0.0001) were significantly associated with the occurrence of cardiovascular events. Our results strongly indicate a relevant prognostic role of structural alterations in small resistance arteries of a high-risk population.
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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
                2008
                December 2007
                26 September 2007
                : 45
                : 1
                : 10-18
                Affiliations
                Departments of aMedical Physics and bPhysiology, Academic Medical Center, University of Amsterdam, and cDepartment of Molecular Cell Biology, Faculty of Medicine, Free University of Amsterdam, Amsterdam, The Netherlands
                Article
                109073 J Vasc Res 2008;45:10–18
                10.1159/000109073
                17898543
                © 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
                Figures: 5, Tables: 1, References: 45, Pages: 9
                Categories
                Research Paper

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