Molecular Mediators of α _vβ ₃-Induced Endothelial Cell Survival

Abstract

The α_vβ₃ integrin interaction with the extracellular matrix (ECM) plays an essential role in inhibiting apoptosis in endothelial cells. We have recently shown that α_vβ₃ ligation on rat aortic endothelial cells (RAECs) specifically activates the transcription factor nuclear factor ĸB (NF-ĸB) and promotes cell survival. Inhibiting NF-ĸB nuclear translocation abolished the protective effect of α_vβ₃ ligands. Here, we report that ligation of α_vβ₃by its ligand, osteopontin (OPN), induces the phosphorylation and activation of inhibitory kappa B kinase beta (IKKβ) and promotes the specific degradation of inhibitory kappa Bα (IĸBα) in RAECs. Overexpression of a dominant negative (DN) IKKβ protein prevents IĸBα phosphorylation, NF-ĸB activation, and inhibits the protective effects of OPN. The NF-ĸB-inducing kinase (NIK) has been shown to be one of the upstream kinases involved in IKK activation. OPN-mediated NF-ĸB activity is increased upon NIK wild-type (WT) overexpression and blocked following NIK DN overexpression. In addition, NIK –/– mouse embryonic fibroblasts (MEFs) plated on OPN display reduced NF-ĸB activity and decreased IĸBα phosphorylation compared to NIK +/+ MEFs. Finally, functional inhibition of integrin β₃-dependent NF-ĸB signaling decreases OPN-induced IĸBα, IKKβ and NIK phosphorylation. These studies for the first time show that the α_vβ₃-NF-ĸB-dependent endothelial survival pathway is dependent on IĸBα, IKKβ, and NIK.

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2006

Publication date (Print): September 2006

Publication date (Electronic): 20 September 2006

Volume: 43

Issue: 5

Pages: 422-436

Affiliations

Departments of ^aPathology and ^bBioengineering, University of Washington, Seattle, Wash., USA

Article

Publisher ID: 94884 Other ID: J Vasc Res 2006;43:422–436

DOI: 10.1159/000094884

PubMed ID: 16888388

Copyright statement: © 2006 S. Karger AG, Basel

License:

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: 8, References: 87, Pages: 15

Product

Self URI (application/pdf): https://www.karger.com/Article/Pdf/94884

Self URI (text/html): https://www.karger.com/Article/FullText/94884

Self URI (journal page): https://www.karger.com/SubjectArea/Cardiovascular-System

Categories

Subject: Research Paper