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      Upregulation of the Water Channel Aquaporin-4 as a Potential Cause of Postischemic Cell Swelling in a Murine Model of Myocardial Infarction

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          Abstract

          Ischemia of the myocardium is generally accepted to be characterized by swelling of myocytes resulting in cardiac dysfunction. However, data are limited concerning the molecular mechanisms of fast water fluxes across cell membranes in ischemic hearts. Since aquaporin-4 (AQP4) is a water channel with an enormous water flux capacity, we investigated in this study whether this water channel protein might play a role in myocyte swelling following myocardial infarction. For this purpose, we studied the expression of AQP4 mRNA at different time points of ischemia in a murine model of myocardial infarction. We observed a significant correlation between the upregulation of AQP4 mRNA and the size of the infarction. In situ hybridization experiments showed comparably higher expression levels of AQP4 mRNA in ischemic myocytes, and anti-AQP4 immunoreactivity was found to be stronger in the sarcolemma of ischemic myocytes. Our findings imply a role of AQP4 in the formation of myocardial edema and this might be important for future prevention and treatment strategies of this distressing situation in order to minimize cardiac dysfunction and mortality in a variety of cardiac diseases in which cell swelling is prevalent.

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          Most cited references 19

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          HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

          Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1 α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.
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            Time course of aquaporin expression after transient focal cerebral ischemia in mice.

            Cerebral edema contributes to morbidity and mortality in stroke. Aquaporins (AQPs)-1, -4, and -9 have been identified as the three main water channels in the brain. To clarify their role in water movement, we have compared their expression patterns with brain swelling after transient focal brain ischemia. There were two peaks of maximal hemispheric swelling at 1 hr and at 48 hr after ischemia, coinciding with two peaks of AQP4 expression. At 1 hr after occlusion, AQP4 expression was significantly increased on astrocyte endfeet in the core and in the border of the lesion. At 48 hr, AQP4 expression was increased in astrocytes in the border of the lesion over the whole cell. AQP9 showed a significant induction at 24 hr that increased gradually with time, without correlation with the swelling. The expression of AQP1 remained unchanged. These results suggest that AQP4, but not AQP1 or AQP9, may play an important role in water movement associated with the pathophysiology of edema after transient cerebral ischemia in the mouse. Copyright 2006 Wiley-Liss, Inc.
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              Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice.

              Cardioprotection by ischemic preconditioning (IP) remains an area of intense investigation. To further elucidate its molecular basis, the use of transgenic mice seems critical. Due to technical difficulty associated with performing cardiac IP in mice, we developed an in situ model for cardiac IP using a hanging-weight system for coronary artery occlusion. This technique has the major advantage of eliminating the necessity of intermittently occluding the coronary artery with a knotted suture. To systematically evaluate this model, we first demonstrated correlation of ischemia times (10-60 min) with infarct sizes [3.5 +/- 1.3 to 42 +/- 5.2% area at risk (AAR), Evan's blue/triphenyltetrazolium chloride staining]. IP (4 x 5 min) and cold ischemia (27 degrees C) reduced infarct size by 69 +/- 6.7% and 84 +/- 4.2%, respectively (n = 6, P < 0.01). In contrast, lower numbers of IP cycles did not alter infarct size. However, infarct sizes were distinctively different in mice from different genetic backgrounds. In addition to infarct staining, we tested cardiac troponin I (cTnI) as marker of myocardial infarction in this model. In fact, plasma levels of cTnI were significantly lower in IP-treated mice and closely correlated with infarct sizes (R(2) = 0.8). To demonstrate transcriptional consequences of cardiac IP, we isolated total RNA from the AAR and showed repression of the equilibrative nucleoside transporters 1-4 by IP in this model. Taken together, this study demonstrates highly reproducible infarct sizes and cardiac protection by IP, thus minimizing the variability associated with knot-based coronary occlusion models. Further studies on cardiac IP using transgenic mice may consider this technique.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2007
                May 2007
                07 February 2007
                : 107
                : 4
                : 402-410
                Affiliations
                aInstitute of Pathology, bDepartment of Anesthesiology and Intensive Care Medicine, and cDepartment of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany
                Article
                99060 Cardiology 2007;107:402–410
                10.1159/000099060
                17284903
                © 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: 7, References: 41, Pages: 9
                Categories
                Original Research

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