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

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          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<sup>12,14</sup>-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-pPhC<sub>6</sub>H<sub>5</sub>), in ECs in vitro. Pretreatment of ECs with DIM-C-pPhC<sub>6</sub>H<sub>5</sub>, 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-pPhC<sub>6</sub>H<sub>5</sub> 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-pPhCH<sub>3</sub>, 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-pPhCH<sub>3</sub> 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.

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          Most cited references 18

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          Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb.

          Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.
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            Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology.

            Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that belong to the steroid/thyroid/retinoic acid receptor superfamily. All their characterized target genes encode proteins that participate in lipid homeostasis. The recent finding that antidiabetic thiazolidinediones and adipogenic prostanoids are ligands of one of the PPARs reveals a novel signaling pathway that directly links these compounds to processes involved in glucose homeostasis and lipid metabolism including adipocyte differentiation. A detailed understanding of this pathway could designate PPARs as targets for the development of novel efficient treatments for several metabolic disorders.
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              Endothelial-leukocyte adhesion molecules.

               M. Bevilacqua (1992)
              One decade ago, vascular endothelium was commonly considered a "non-stick" lining of blood vessels that functioned only to prevent blood coagulation and to separate the vascular space from tissues. By comparison to many other cell types, endothelial cells were thought to be less active, less complex, and less interesting. Since that time, research concerning the endothelium has expanded dramatically and produced a new image of the vascular lining as an active participant in a wide variety of pathophysiological processes, including inflammation and immunity. Nowhere has the excitement been more intense than in the study of the molecular mechanisms of leukocyte adhesion to endothelium. Recent efforts resulted in the identification, characterization, and cloning of multiple endothelial cell-surface glycoproteins that support adhesion through an interaction with specific ligands (or counter-receptors) on leukocytes. The selectins, two of which are found on endothelium and one on leukocytes, support adhesion through the recognition of carbohydrates. Endothelial members of the immunoglobulin superfamily including ICAM-1 and VCAM-1/INCAM-110 bind to leukocyte cell-surface integrins. In various combinations, these and other molecules support leukocyte adhesion to the vessel wall and extravasation, key steps in our response to infection and tissue injury.
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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
                2005
                December 2005
                20 October 2005
                : 42
                : 6
                : 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
                88260 J Vasc Res 2005;42:509–516
                10.1159/000088260
                16155367
                © 2005 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: 4, References: 33, Pages: 8
                Categories
                Research Paper

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