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Table of Contents
Vol. 113, No. 4, 2009
Issue release date: July 2009
Section title: Original Research
Cardiology 2009;113:291–298
(DOI:10.1159/000209256)

Fibronectin Gene Expression in Aortic Regurgitation: Relative Roles of Mitogen-Activated Protein Kinases

Truter S.L. · Catanzaro D.F. · Supino P.G. · Gupta A. · Carter J. · Ene A.R. · Herrold E.M. · Dumlao T.F. · Beltran F. · Borer J.S.
aWyeth Research, Collegeville, Pa., bThe Division of Cardiovascular Medicine and The Howard Gilman Institute for Heart Valve Disease, State University of New York Downstate Medical Center, Brooklyn, N.Y., cColumbia University Medical Center, New York, N.Y., and dBoston Medical Center, South Boston, Mass., USA

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Article / Publication Details

First-Page Preview
Abstract of Original Research

Received: 12/19/2008
Accepted: 12/31/2008
Published online: 3/20/2009

Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 0

ISSN: 0008-6312 (Print)
eISSN: 1421-9751 (Online)

For additional information: http://www.karger.com/CRD

Abstract

Objectives: In aortic regurgitation (AR), fibronectin (FN) expression is upregulated. This study sought to determine signal transduction pathways involved in upregulation of FN expression in AR. Methods: Cardiac fibroblasts (CF) from rabbits with surgically induced AR and matched controls (NL) were cultured and assayed for FN expression and kinase activity with and without inhibitors of kinases JNK, p38 mitogen-activated protein kinase (MAPK) and extracellular response kinase (ERK). NL CF also were subjected to cyclic strain mimicking AR for 24 h in culture with and without inhibitors. Results: AR CF exhibited 2.9-fold greater c-Jun phosphorylation (p < 0.01) and 1.5- to 2-fold greater ATF2 phosphorylation (p < 0.05–0.01) than NL. JNK and p38MAPK inhibition reduced c-Jun and ATF2 phosphorylation to NL; ERK inhibition had no effect. FN mRNA expression was similar in pattern to kinase activities. Cyclic strain in NL CF increased c-Jun phosphorylation 2-fold versus unstrained controls (p < 0.005). This was suppressed by inhibition of JNK but not p38MAPK. Conclusion: FN expression in response to the acute mechanical strain resembling AR is upregulated primarily via JNK. However, in chronic AR both JNK and p38MAPK are involved. These signaling pathways represent potential therapeutic targets for normalizing extracellular matrix (ECM) composition and contractile force transmission, believed to be related to ECM composition/organization, in AR.


Article / Publication Details

First-Page Preview
Abstract of Original Research

Received: 12/19/2008
Accepted: 12/31/2008
Published online: 3/20/2009

Number of Print Pages: 8
Number of Figures: 3
Number of Tables: 0

ISSN: 0008-6312 (Print)
eISSN: 1421-9751 (Online)

For additional information: http://www.karger.com/CRD


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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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.
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