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Short Communication |
(PPAR) Expression and Reduction of MMP-9 Activitythrough PPAR Activation in Mononuclear Phagocytes inVitro
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Mononuclear phagocytes play an important role in atherosclerosis
and its sequela plaque rupture in part by their secretion of matrix
metalloproteinases (MMPs), including MMP-9. Peroxisomal
proliferator-activated receptor 
(PPAR), a transcription
factor in the nuclear receptor superfamily, regulates gene
expression in response to various activators, including
15-deoxy-
12,14-prostaglandin J2 and
the antidiabetic agent troglitazone. The role of PPAR in human
atherosclerosis is unexplored. We report here that
monocytes/macrophages in human atherosclerotic lesions
(n = 12) express immunostainable PPAR. Normal
artery specimens (n = 6) reveal minimal
immunoreactive PPAR. Human monocytes and monocyte-derived
macrophages cultured for 6 days in 5% human serum expressed PPAR
mRNA and protein by reverse transcription-polymerase chain reaction and
Western blotting, respectively. In addition, PPAR
mRNA expression in U937 cells increased during phorbol 12-myristate 13
acetate-induced differentiation. Stimulation of PPAR with
troglitazone or 15-deoxy-12,14-prostaglandin
J2 in human monocyte-derived macrophages inhibited MMP-9
gelatinolytic activity in a concentration-dependent fashion as revealed
by zymography. This inhibition correlates with decreased MMP-9
secretion as determined by Western blotting. Thus, PPAR is
present in macrophages in human atherosclerotic lesions and may
regulate expression and activity of MMP-9, an enzyme implicated
in plaque rupture. PPAR is likely to be an important regulator of
monocyte/macrophage function with relevance for human atherosclerotic
disease.
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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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 C. M. Komar and T. E. Curry Jr Localization and Expression of Messenger RNAs for the Peroxisome Proliferator-Activated Receptors in Ovarian Tissue from Naturally Cycling and Pseudopregnant Rats Biol Reprod, May 1, 2002; 66(5): 1531 - 1539. [Abstract] [Full Text]
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 T. E. Akiyama, S. Sakai, G. Lambert, C. J. Nicol, K. Matsusue, S. Pimprale, Y.-H. Lee, M. Ricote, C. K. Glass, H. B. Brewer Jr., et al. Conditional Disruption of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux Mol. Cell. Biol., April 15, 2002; 22(8): 2607 - 2619. [Abstract] [Full Text] [PDF]
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A. V. Pontsler, A. St. Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre Cyclooxygenase-2 Is Induced in Monocytes by Peroxisome Proliferator Activated Receptor gamma and Oxidized Alkyl Phospholipids from Oxidized Low Density Lipoprotein J. Biol. Chem., April 5, 2002; 277(15): 13029 - 13036. [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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R. L. Schild, W. T. Schaiff, M. G. Carlson, E. J. Cronbach, D. M. Nelson, and Y. Sadovsky The Activity of PPAR{gamma} in Primary Human Trophoblasts Is Enhanced by Oxidized Lipids J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1105 - 1110. [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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Y. Oyama, N. Akuzawa, R. Nagai, and M. Kurabayashi PPAR{gamma} Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells Circ. Res., February 22, 2002; 90(3): 348 - 355. [Abstract] [Full Text] [PDF]
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B. R. Kwak, S. Myit, F. Mulhaupt, N. Veillard, N. Rufer, E. Roosnek, and F. Mach PPAR{gamma} but not PPAR{alpha} Ligands Are Potent Repressors of Major Histocompatibility Complex Class II Induction in Atheroma-Associated Cells Circ. Res., February 22, 2002; 90(3): 356 - 362. [Abstract] [Full Text] [PDF]
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 D J Grainger and H W L Bethell High titres of serum antinuclear antibodies, mostly directed against nucleolar antigens, are associated with the presence of coronary atherosclerosis Ann Rheum Dis, February 1, 2002; 61(2): 110 - 114. [Abstract] [Full Text] [PDF]
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W. A. Hsueh and R. E. Law PPAR{gamma} and Atherosclerosis: Effects on Cell Growth and Movement Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1891 - 1895. [Abstract] [Full Text] [PDF]
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C. M. Komar, O. Braissant, W. Wahli, and T. E. Curry Jr. Expression and Localization of PPARs in the Rat Ovary During Follicular Development and the Periovulatory Period Endocrinology, November 1, 2001; 142(11): 4831 - 4838. [Abstract] [Full Text] [PDF]
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 L. BENAYOUN, S. LETUVE, A. DRUILHE, J. BOCZKOWSKI, M.-C. DOMBRET, P. MECHIGHEL, J. MEGRET, G. LESECHE, M. AUBIER, and M. PRETOLANI Regulation of Peroxisome Proliferator-activated Receptor gamma Expression in Human Asthmatic Airways . Relationship with Proliferation, Apoptosis, and Airway Remodeling Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1487 - 1494. [Abstract] [Full Text] [PDF]
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 J S Sidhu and J C Kaski Peroxisome proliferator activated receptor {gamma}: a potential therapeutic target in the management of ischaemic heart disease Heart, September 1, 2001; 86(3): 255 - 258. [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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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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H. Ghanim, R. Garg, A. Aljada, P. Mohanty, Y. Kumbkarni, E. Assian, W. Hamouda, and P. Dandona Suppression of Nuclear Factor-{{kappa}}B and Stimulation of Inhibitor {{kappa}}B by Troglitazone: Evidence for an Anti-inflammatory Effect and a Potential Antiatherosclerotic Effect in the Obese J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1306 - 1312. [Abstract] [Full Text]
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 T. Claudel, M. D. Leibowitz, C. Fiévet, A. Tailleux, B. Wagner, J. J. Repa, G. Torpier, J.-M. Lobaccaro, J. R. Paterniti, D. J. Mangelsdorf, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor PNAS, February 15, 2001; (2001) 41609298. [Abstract] [Full Text]
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W. A. Hsueh, S. Jackson, and R. E. Law Control of Vascular Cell Proliferation and Migration by PPAR-{gamma}: A new approach to the macrovascular complications of diabetes Diabetes Care, February 1, 2001; 24(2): 392 - 397. [Abstract] [Full Text]
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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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 A. A. Parulkar, M. L. Pendergrass, R. Granda-Ayala, T. R. Lee, and V. A. Fonseca Nonhypoglycemic Effects of Thiazolidinediones Ann Intern Med, January 2, 2001; 134(1): 61 - 71. [Abstract] [Full Text] [PDF]
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 T. Murata, S. He, M. Hangai, T. Ishibashi, X.-P. Xi, S. Kim, W. A. Hsueh, S. J. Ryan, R. E. Law, and D. R. Hinton Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit Choroidal Neovascularization Invest. Ophthalmol. Vis. Sci., July 1, 2000; 41(8): 2309 - 2317. [Abstract] [Full Text]
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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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U. Ikeda, M. Shimpo, Y. Murakami, and K. Shimada Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit Nitric Oxide Synthesis in Vascular Smooth Muscle Cells Hypertension, June 1, 2000; 35(6): 1232 - 1236. [Abstract] [Full Text] [PDF]
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 C. Huin, L. Corriveau, A. Bianchi, J. M. Keller, P. Collet, P. Krémarik-Bouillaud, L. Domenjoud, P. Bécuwe, H. Schohn, D. Ménard, et al. Differential Expression of Peroxisome Proliferator-activated Receptors (PPARs) in the Developing Human Fetal Digestive Tract J. Histochem. Cytochem., May 1, 2000; 48(5): 603 - 612. [Abstract] [Full Text]
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R. E. Law, S. Goetze, X.-P. Xi, S. Jackson, Y. Kawano, L. Demer, M. C. Fishbein, W. P. Meehan, and W. A. Hsueh Expression and Function of PPAR{gamma} in Rat and Human Vascular Smooth Muscle Cells Circulation, March 21, 2000; 101(11): 1311 - 1318. [Abstract] [Full Text] [PDF]
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A. Castrillo, M. J. M. Díaz-Guerra, S. Hortelano, P. Martín-Sanz, and L. Boscá Inhibition of Ikappa B Kinase and Ikappa B Phosphorylation by 15-Deoxy-Delta 12,14-Prostaglandin J2 in Activated Murine Macrophages Mol. Cell. Biol., March 1, 2000; 20(5): 1692 - 1698. [Abstract] [Full Text]
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R. Thieringer, J. E. Fenyk-Melody, C. B. Le Grand, B. A. Shelton, P. A. Detmers, E. P. Somers, L. Carbin, D. E. Moller, S. D. Wright, and J. Berger Activation of Peroxisome Proliferator-Activated Receptor {gamma} Does Not Inhibit IL-6 or TNF-{alpha} Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo J. Immunol., January 15, 2000; 164(2): 1046 - 1054. [Abstract] [Full Text] [PDF]
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M. R. Sartippour and G. Renier Differential Regulation of Macrophage Peroxisome Proliferator-Activated Receptor Expression by Glucose : Role of Peroxisome Proliferator-Activated Receptors in Lipoprotein Lipase Gene Expression Arterioscler Thromb Vasc Biol, January 1, 2000; 20(1): 104 - 110. [Abstract] [Full Text] [PDF]
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