Inhibition of Tumor-Necrosis-Factor-αDELETEInduced Endothelial Cell Activation by a New Class of PPAR-γ Agonists

Abstract

Proinflammatory cytokines and adhesion molecules expressed by endothelial cells (ECs) play a critical role in initiating and promoting atherosclerosis. Agents that oppose these inflammatory effects in vascular cells include peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, including 15-deoxy-δ^12,14-prostaglandin J2 (15d-PGJ2) and synthetic thiazolidinediones. Recently, a new structural class of potent PPAR-γ agonists, 1,1-bis(3′-indolyl)-1-( p-substituted phenyl) methanes, has been characterized. The purpose of this study was to evaluate the anti-inflammatory effects of two PPAR-γ-active members of this class, 1,1-bis(3′-indolyl)-1-( p-t-butylphenyl)methane (DIM-C-pPhtBu) and 1,1-bis(3′-indolyl)-1-( p-biphenyl)methane (DIM-C-pPhC₆H₅), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC₆H₅, DIM-C- pPhtBu, or 15d-PGJ2 decreased tumor necrosis factor-α (TNF-α)-induced intercellular adhesion molecule (ICAM)-1 expression in a concentration-dependent manner. At a concentration of 10 µ M, DIM-C-pPhtBu and DIM-C-pPhC₆H₅ decreased ICAM-1 expression by 77.5 and 71.3%, respectively, and comparable inhibition (84.4%) was observed for 10 µ M 15d-PGJ2 (p < 0.05). In contrast, 10 µ M ciglitazone and DIM-C-pPhCH₃, which exhibits low PPAR-γ agonist activity, were inactive. The two new PPAR-γ agonists and 15d-PGJ2 also inhibited TNF-α-induced interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) production in supernatants of TNF-α-stimulated ECs, whereas ciglitazone and DIM-C-pPhCH₃ did not decrease TNF-α-induced expression of these two proteins. This new structural class of PPAR-γ agonists inhibited the expression of ICAM-1 and the production of IL-6 and MCP-1 in TNF-α-activated ECs at lower concentrations than other synthetic PPAR-γ agonists, suggesting the potential clinical utility of 1,1-bis(3′-indolyl)-1-( p-substituted phenyl) methanes for decreasing endothelial inflammation.

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: 2005

Publication date (Print): December 2005

Publication date (Electronic): 20 October 2005

Volume: 42

Issue: 6

Pages: 509-516

Affiliations

^aBrown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Houston Health Science Center, ^bTexas Heart Institute, St Luke’s Episcopal Hospital, ^cInstitute of Biosciences and Technology, Texas A&M University System, and ^dDepartment of Cardiology, M.D. Anderson Cancer Center, University of Texas, Houston, Tex., USA

Article

Publisher ID: 88260 Other ID: J Vasc Res 2005;42:509–516

DOI: 10.1159/000088260

PubMed ID: 16155367

Copyright statement: © 2005 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: 4, References: 33, Pages: 8

Product

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Categories

Subject: Research Paper