(Circulation. 1999;99:3125-3131.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
PPAR
Activators Inhibit Cytokine-Induced Vascular Cell Adhesion Molecule-1 Expression in Human Endothelial Cells
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division (N.M., G.K.S., P.L., J.P.) and the Vascular Research Division, Department of Pathology (T.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Jorge Plutzky, MD, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115. E-mail jplutzky{at}rics.bwh.harvard.edu
Background—Adhesion molecule
expression on the endothelial cell (EC) surface is
critical for leukocyte recruitment to atherosclerotic lesions. Better
understanding of transcriptional regulation of adhesion molecules in
ECs may provide important insight into plaque formation. Peroxisome
proliferator–activated receptor-
(PPAR), a member of the
nuclear receptor family, regulates gene expression in response to
certain fatty acids and fibric acid derivatives. The present study
investigated PPAR expression in human ECs and their regulation of
vascular cell adhesion molecule-1 (VCAM-1).
Methods and Results—Immunohistochemistry revealed that human
carotid artery ECs express PPAR. Pretreatment of cultured human ECs
with the PPAR activators fenofibrate or WY14643
inhibited TNF-–induced VCAM-1 in a time- and
concentration-dependent manner, an effect not seen with PPAR
activators. Both PPAR activators decreased
cytokine-induced VCAM-1 mRNA expression without altering
its mRNA half-life. Transient transfection of deletional VCAM-1
promoter constructs and electrophoretic mobility shift assays suggest
that fenofibrate inhibits VCAM-1 transcription in part by inhibiting
NF-
B. Finally, PPAR activators significantly reduced
adhesion of U937 cells to cultured human ECs.
Conclusions—Human ECs express PPAR, a potentially important
regulator of atherogenesis through its transcriptional control of
VCAM-1 gene expression. Such findings also have implications regarding
the clinical use of lipid-lowering agents, like fibric acids, which can
activate PPAR.
Key Words: atherosclerosis • endothelium • leukocytes
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 C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]
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 D. M. Tham, B. Martin-McNulty, Y.-x. Wang, D. W. Wilson, R. Vergona, M. E. Sullivan, W. Dole, and J. C. Rutledge Angiotensin II is associated with activation of NF-{kappa}B-mediated genes and downregulation of PPARs Physiol Genomics, October 2, 2002; 11(1): 21 - 30. [Abstract] [Full Text] [PDF]
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E. Cernuda-Morollon, F. Rodriguez-Pascual, P. Klatt, S. Lamas, and D. Perez-Sala PPAR Agonists Amplify iNOS Expression While Inhibiting NF-{kappa}B: Implications for Mesangial Cell Activation by Cytokines J. Am. Soc. Nephrol., September 1, 2002; 13(9): 2223 - 2231. [Abstract] [Full Text] [PDF]
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 S. Sethi, O. Ziouzenkova, H. Ni, D. D. Wagner, J. Plutzky, and T. N. Mayadas Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPARalpha Blood, July 30, 2002; 100(4): 1340 - 1346. [Abstract] [Full Text] [PDF]
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 J. A. Beckman, M. A. Creager, and P. Libby Diabetes and Atherosclerosis: Epidemiology, Pathophysiology, and Management JAMA, May 15, 2002; 287(19): 2570 - 2581. [Abstract] [Full Text] [PDF]
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 P. Delerive, K. De Bosscher, W. Vanden Berghe, J.-C. Fruchart, G. Haegeman, and B. Staels DNA Binding-Independent Induction of I{kappa}B{alpha} Gene Transcription by PPAR{alpha} Mol. Endocrinol., May 1, 2002; 16(5): 1029 - 1039. [Abstract] [Full Text] [PDF]
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O. Barbier, I. P. Torra, Y. Duguay, C. Blanquart, J.-C. Fruchart, C. Glineur, and B. Staels Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors in Lipid Metabolism and Atherosclerosis Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 717 - 726. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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G. J. Etgen, B. A. Oldham, W. T. Johnson, C. L. Broderick, C. R. Montrose, J. T. Brozinick, E. A. Misener, J. S. Bean, W. R. Bensch, D. A. Brooks, et al. A Tailored Therapy for the Metabolic Syndrome : The Dual Peroxisome Proliferator-Activated Receptor-{alpha}/{gamma} Agonist LY465608 Ameliorates Insulin Resistance and Diabetic Hyperglycemia While Improving Cardiovascular Risk Factors in Preclinical Models Diabetes, April 1, 2002; 51(4): 1083 - 1087. [Abstract] [Full Text] [PDF]
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R. Cunard, M. Ricote, D. DiCampli, D. C. Archer, D. A. Kahn, C. K. Glass, and C. J. Kelly Regulation of Cytokine Expression by Ligands of Peroxisome Proliferator Activated Receptors J. Immunol., March 15, 2002; 168(6): 2795 - 2802. [Abstract] [Full Text] [PDF]
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R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
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D. P. Kelly The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway Circ. Res., November 23, 2001; 89(11): 935 - 937. [Full Text] [PDF]
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 P. Amarenco Hypercholesterolemia, lipid-lowering agents, and the risk for brain infarction Neurology, September 1, 2001; 57(90002): S35 - 44. [Abstract] [Full Text]
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 K. Fujimoto, T. Imaizumi, H. Yoshida, S. Takanashi, K. Okumura, and K. Satoh Interferon-gamma Stimulates Fractalkine Expression in Human Bronchial Epithelial Cells and Regulates Mononuclear Cell Adherence Am. J. Respir. Cell Mol. Biol., August 1, 2001; 25(2): 233 - 238. [Abstract] [Full Text] [PDF]
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X. Xu, M. Otsuki, H. Saito, S. Sumitani, H. Yamamoto, N. Asanuma, H. Kouhara, and S. Kasayama PPAR{alpha} and GR Differentially Down-Regulate the Expression of Nuclear Factor-{kappa}B-Responsive Genes in Vascular Endothelial Cells Endocrinology, August 1, 2001; 142(8): 3332 - 3339. [Abstract] [Full Text] [PDF]
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]
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H. Bloomfield Rubins, J. Davenport, V. Babikian, L. M. Brass, D. Collins, L. Wexler, S. Wagner, V. Papademetriou, G. Rutan, and S. J. Robins Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol : The Veterans Affairs HDL Intervention Trial (VA-HIT) Circulation, June 12, 2001; 103(23): 2828 - 2833. [Abstract] [Full Text] [PDF]
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V. Pasceri, J. Chang, J. T. Willerson, and E. T. H. Yeh Modulation of C-Reactive Protein-Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs Circulation, May 29, 2001; 103(21): 2531 - 2534. [Abstract] [Full Text] [PDF]
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A. Tedgui and Z. Mallat Anti-Inflammatory Mechanisms in the Vascular Wall Circ. Res., May 11, 2001; 88(9): 877 - 887. [Abstract] [Full Text] [PDF]
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 C. S. Elangbam, R. D. Tyler, and R. M. Lightfoot Peroxisome Proliferator-activated Receptors in Atherosclerosis and Inflammation--An Update Toxicol Pathol, February 1, 2001; 29(2): 224 - 231. [Abstract] [PDF]
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M. Otsuki, H. Saito, X. Xu, S. Sumitani, H. Kouhara, T. Kishimoto, and S. Kasayama Progesterone, but Not Medroxyprogesterone, Inhibits Vascular Cell Adhesion Molecule-1 Expression in Human Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 243 - 248. [Abstract] [Full Text] [PDF]
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J. Plutzky and P. M. Ridker Statins for Stroke: The Second Story? Circulation, January 23, 2001; 103(3): 348 - 350. [Full Text] [PDF]
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B. P. Neve, D. Corseaux, G. Chinetti, C. Zawadzki, J.-C. Fruchart, P. Duriez, B. Staels, and B. Jude PPAR{{alpha}} Agonists Inhibit Tissue Factor Expression in Human Monocytes and Macrophages Circulation, January 16, 2001; 103(2): 207 - 212. [Abstract] [Full Text] [PDF]
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N. Marx, N. Mackman, U. Schonbeck, N. Yilmaz, V. Hombach, P. Libby, and J. Plutzky PPAR{{alpha}} Activators Inhibit Tissue Factor Expression and Activity in Human Monocytes Circulation, January 16, 2001; 103(2): 213 - 219. [Abstract] [Full Text] [PDF]
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Rainer de Martin, M. Hoeth, R. Hofer-Warbinek, and J. A. Schmid The Transcription Factor NF-{kappa}B and the Regulation of Vascular Cell Function Arterioscler Thromb Vasc Biol, November 1, 2000; 20 (11): e83 - e88. [Abstract] [Full Text] [PDF]
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H. Takano, T. Nagai, M. Asakawa, T. Toyozaki, T. Oka, I. Komuro, T. Saito, and Y. Masuda Peroxisome Proliferator-Activated Receptor Activators Inhibit Lipopolysaccharide-Induced Tumor Necrosis Factor-{alpha} Expression in Neonatal Rat Cardiac Myocytes Circ. Res., September 29, 2000; 87(7): 596 - 602. [Abstract] [Full Text] [PDF]
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N. Marx, F. Mach, A. Sauty, J. H. Leung, M. N. Sarafi, R. M. Ransohoff, P. Libby, J. Plutzky, and A. D. Luster Peroxisome Proliferator-Activated Receptor-{gamma} Activators Inhibit IFN-{gamma}-Induced Expression of the T Cell-Active CXC Chemokines IP-10, Mig, and I-TAC in Human Endothelial Cells J. Immunol., June 15, 2000; 164(12): 6503 - 6508. [Abstract] [Full Text] [PDF]
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V. Pasceri, H. D. Wu, J. T. Willerson, and E. T. H. Yeh Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator-Activated Receptor-{gamma} Activators Circulation, January 25, 2000; 101(3): 235 - 238. [Abstract] [Full Text] [PDF]
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P. Delerive, K. De Bosscher, S. Besnard, W. Vanden Berghe, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, A. Tedgui, G. Haegeman, and B. Staels Peroxisome Proliferator-activated Receptor alpha Negatively Regulates the Vascular Inflammatory Gene Response by Negative Cross-talk with Transcription Factors NF-kappa B and AP-1 J. Biol. Chem., November 5, 1999; 274(45): 32048 - 32054. [Abstract] [Full Text] [PDF]
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P. Delerive, P. Gervois, J.-C. Fruchart, and B. Staels Induction of Ikappa Balpha Expression as a Mechanism Contributing to the Anti-inflammatory Activities of Peroxisome Proliferator-activated Receptor-alpha Activators J. Biol. Chem., November 17, 2000; 275(47): 36703 - 36707. [Abstract] [Full Text] [PDF]
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P. Gervois, N. Vu-Dac, R. Kleemann, M. Kockx, G. Dubois, B. Laine, V. Kosykh, J.-C. Fruchart, T. Kooistra, and B. Staels Negative Regulation of Human Fibrinogen Gene Expression by Peroxisome Proliferator-activated Receptor alpha Agonists via Inhibition of CCAAT Box/Enhancer-binding Protein beta J. Biol. Chem., August 31, 2001; 276(36): 33471 - 33477. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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D. M. Flavell, Y. Jamshidi, E. Hawe, I. Pineda Torra, M.-R. Taskinen, M. H. Frick, M. S. Nieminen, Y. A. Kesaniemi, A. Pasternack, B. Staels, et al. Peroxisome Proliferator-Activated Receptor {alpha} Gene Variants Influence Progression of Coronary Atherosclerosis and Risk of Coronary Artery Disease Circulation, March 26, 2002; 105(12): 1440 - 1445. [Abstract] [Full Text] [PDF]
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