© 1999 American Heart Association, Inc.
Molecular Medicine |
Peroxisome Proliferator-Activated Receptor Activators Inhibit Thrombin-Induced Endothelin-1 Production in Human Vascular Endothelial Cells by Inhibiting the Activator Protein-1 Signaling Pathway
From the U.325 INSERM (P.D., F.M.-N., G.C., J.-C.F., J.N., P.D., B.S.), Département d'Athérosclérose, Institut Pasteur de Lille, Lille, France, and the Faculté de Pharmacie, Université de Lille II, Lille, France; and U.167 INSERM (F.T.), Centre d'Immunologie et de Biologie Parasitaire, Institut Pasteur de Lille, Lille, France.
Correspondence to Prof Bart Staels, U.325 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille, 1 Rue Calmette BP245, 59019 Lille, France. E-mail Bart.Staels{at}pasteur-lille.fr
Abstract—Endothelin-1 (ET-1), a
21-amino acid vasoactive peptide mainly produced by vascular
endothelial cells, is involved in the regulation of
vascular tone and smooth muscle cell proliferation. Peroxisome
proliferator-activated receptors (PPARs), key players in lipid
and glucose metabolism, have been implicated in
metabolic disorders that are predisposing to
atherosclerosis. Because of the potential role of ET-1
in vascular disorders such as hypertension and
atherosclerosis, we investigated the regulation of ET-1
expression by PPAR activators. Western blot and reverse
transcription–polymerase chain reaction analyses demonstrated
that both PPAR
and PPAR
are expressed in human coronary
artery endothelial cells as well as in
endothelial cell lines such as HMEC-1 and ECV304. In
bovine aortic endothelial cells and HMEC-1 cells, both
PPAR and PPAR ligands inhibited thrombin-induced ET-1 secretion,
whereas basal ET-1 secretion was only slightly suppressed. Reverse
transcription–polymerase chain reaction experiments showed that this
inhibition of ET-1 production occurs at the gene expression
level. Using transient transfection assays, we demonstrated that PPARs
downregulate thrombin-activated transcription of the human ET-1
promoter. Transactivation studies with c-Jun and c-Fos expression
plasmids indicated that PPARs negatively interfere with the
activator protein-1 signaling pathway, which mediates
thrombin activation of ET-1 gene transcription. Furthermore,
electrophoretic mobility shift assays demonstrated that PPAR
activators reduce the thrombin-stimulated binding activity
of bovine aortic endothelial cell nuclear extracts as
well as c-Jun binding to an activator protein-1 consensus
site. Taken together, these data indicate that (1) both PPAR and
PPAR are expressed in human vascular endothelial
cells and (2) PPAR activators inhibit thrombin-induced ET-1
biosynthesis, indicating a novel role for PPARs in vascular
endothelial function.
Key Words: peroxisome proliferator-activated receptor • endothelin • thrombin • atherosclerosis • endothelium
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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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W. Eberhardt, E.-S. Akool, J. Rebhan, S. Frank, K.-F. Beck, R. Franzen, F. M. A. Hamada, and J. Pfeilschifter Inhibition of Cytokine-induced Matrix Metalloproteinase 9 Expression by Peroxisome Proliferator-activated Receptor alpha Agonists Is Indirect and Due to a NO-mediated Reduction of mRNA Stability J. Biol. Chem., August 30, 2002; 277(36): 33518 - 33528. [Abstract] [Full Text] [PDF]
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 C. S. Elangbam, T. A. Brodie, H. Roger Brown, J. B. Nold, T. J. Raczniak, R. D. Tyler, R. M. Lightfoot, and H. G. Wall Vascular Effects of GI262570X (PPAR-{gamma} agonist) in the Brown Adipose Tissue of Han Wistar Rats: A Review of 1-month, 13-week, 27-week and 2-year Oral Toxicity Studies Toxicol Pathol, June 1, 2002; 30(4): 420 - 426. [Abstract] [PDF]
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Q. N. Diep, M. El Mabrouk, J. S. Cohn, D. Endemann, F. Amiri, A. Virdis, M. F. Neves, and E. L. Schiffrin Structure, Endothelial Function, Cell Growth, and Inflammation in Blood Vessels of Angiotensin II-Infused Rats: Role of Peroxisome Proliferator-Activated Receptor-{gamma} Circulation, May 14, 2002; 105(19): 2296 - 2302. [Abstract] [Full Text] [PDF]
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N. Khandoudi, P. Delerive, I. Berrebi-Bertrand, R. E. Buckingham, B. Staels, and A. Bril Rosiglitazone, a Peroxisome Proliferator-Activated Receptor-{gamma}, Inhibits the Jun NH2-Terminal Kinase/Activating Protein 1 Pathway and Protects the Heart From Ischemia/Reperfusion Injury Diabetes, May 1, 2002; 51(5): 1507 - 1514. [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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T. Kaneko, S. Fujii, A. Matsumoto, D. Goto, N. Ishimori, K. Watano, T. Furumoto, T. Sugawara, B. E. Sobel, and A. Kitabatake Induction of Plasminogen Activator Inhibitor-1 in Endothelial Cells by Basic Fibroblast Growth Factor and Its Modulation by Fibric Acid Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 855 - 860. [Abstract] [Full Text] [PDF]
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P. Quehenberger, M. Exner, R. Sunder-Plassmann, K. Ruzicka, C. Bieglmayer, G. Endler, C. Muellner, W. Speiser, and O. Wagner Leptin Induces Endothelin-1 in Endothelial Cells In Vitro Circ. Res., April 5, 2002; 90(6): 711 - 718. [Abstract] [Full Text] [PDF]
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N. Frey and E. N. Olson Modulating Cardiac Hypertrophy by Manipulating Myocardial Lipid Metabolism? Circulation, March 12, 2002; 105(10): 1152 - 1154. [Full Text] [PDF]
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 B. Molavi, N. Rasouli, and J. L. Mehta Peroxisome Proliferator-Activated Receptor Ligands as Antiatherogenic Agents: Panacea or Another Pandora's Box? Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2002; 7(1): 1 - 8. [Abstract] [PDF]
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A. Masamune, K. Kikuta, M. Satoh, Y. Sakai, A. Satoh, and T. Shimosegawa Ligands of Peroxisome Proliferator-activated Receptor-gamma Block Activation of Pancreatic Stellate Cells J. Biol. Chem., January 4, 2002; 277(1): 141 - 147. [Abstract] [Full Text]
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Q. N. Diep and E. L. Schiffrin Increased Expression of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} in Blood Vessels of Spontaneously Hypertensive Rats Hypertension, August 1, 2001; 38(2): 249 - 254. [Abstract] [Full Text] [PDF]
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A. Aljada, H. Ghanim, J. Friedman, R. Garg, P. Mohanty, and P. Dandona Troglitazone Reduces the Expression of PPAR{{gamma}} While Stimulating That of PPAR{{alpha}} in Mononuclear Cells in Obese Subjects J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3130 - 3133. [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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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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A. T. KOVALA, K. A. HARVEY, P. McGLYNN, G. BOGUSLAWSKI, J. G. N. GARCIA, and D. ENGLISH High-efficiency transient transfection of endothelial cells for functional analysis FASEB J, December 1, 2000; 14(15): 2486 - 2494. [Abstract] [Full Text]
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 J.-i. Hisatake, T. Ikezoe, M. Carey, S. Holden, S. Tomoyasu, and H. P. Koeffler Down-Regulation of Prostate-specific Antigen Expression by Ligands for Peroxisome Proliferator-activated Receptor {{gamma}} in Human Prostate Cancer Cancer Res., October 1, 2000; 60(19): 5494 - 5498. [Abstract] [Full Text]
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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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D. Lepailleur-Enouf, O. Valdenaire, M. Philippe, M. Jandrot-Perrus, and J.-B. Michel Thrombin induces endothelin expression in arterial smooth muscle cells Am J Physiol Heart Circ Physiol, May 1, 2000; 278(5): H1606 - H1612. [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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Y. Ikeda, A. Sugawara, Y. Taniyama, A. Uruno, K. Igarashi, S. Arima, S. Ito, and K. Takeuchi Suppression of Rat Thromboxane Synthase Gene Transcription by Peroxisome Proliferator-activated Receptor gamma in Macrophages via an Interaction with NRF2 J. Biol. Chem., October 13, 2000; 275(42): 33142 - 33150. [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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S. Wakino, U. Kintscher, S. Kim, F. Yin, W. A. Hsueh, and R. E. Law Peroxisome Proliferator-activated Receptor gamma Ligands Inhibit Retinoblastoma Phosphorylation and G1right-arrow S Transition in Vascular Smooth Muscle Cells J. Biol. Chem., July 14, 2000; 275(29): 22435 - 22441. [Abstract] [Full Text] [PDF]
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 F. Zheng, A. Fornoni, S. J. Elliot, Y. Guan, M. D. Breyer, L. J. Striker, and G. E. Striker Upregulation of type I collagen by TGF-beta in mesangial cells is blocked by PPARgamma activation Am J Physiol Renal Physiol, April 1, 2002; 282(4): F639 - F648. [Abstract] [Full Text] [PDF]
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M. Asakawa, H. Takano, T. Nagai, H. Uozumi, H. Hasegawa, N. Kubota, T. Saito, Y. Masuda, T. Kadowaki, and I. Komuro Peroxisome Proliferator-Activated Receptor {gamma} Plays a Critical Role in Inhibition of Cardiac Hypertrophy In Vitro and In Vivo Circulation, March 12, 2002; 105(10): 1240 - 1246. [Abstract] [Full Text] [PDF]
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P. Quehenberger, M. Exner, R. Sunder-Plassmann, K. Ruzicka, C. Bieglmayer, G. Endler, C. Muellner, W. Speiser, and O. Wagner Leptin Induces Endothelin-1 in Endothelial Cells In Vitro Circ. Res., April 5, 2002; 90(6): 711 - 718. [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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