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*12-O-TETRADECANOYLPHORBOL-13-ACETATE
(American Journal of Pathology. 1998;153:17-23.)
© 1998 American Society for Investigative Pathology


Short Communication

Macrophages in Human Atheroma Contain PPAR{gamma}

Differentiation-Dependent Peroxisomal Proliferator-ActivatedReceptor {gamma} (PPAR{gamma}) Expression and Reduction of MMP-9 Activitythrough PPAR{gamma} Activation in Mononuclear Phagocytes inVitro

Nikolaus Marx, Galina Sukhova, Curran Murphy, Peter Libby and Jorge Plutzky

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 {gamma} (PPAR{gamma}), a transcription factor in the nuclear receptor superfamily, regulates gene expression in response to various activators, including 15-deoxy-{Delta}12,14-prostaglandin J2 and the antidiabetic agent troglitazone. The role of PPAR{gamma} in human atherosclerosis is unexplored. We report here that monocytes/macrophages in human atherosclerotic lesions (n = 12) express immunostainable PPAR{gamma}. Normal artery specimens (n = 6) reveal minimal immunoreactive PPAR{gamma}. Human monocytes and monocyte-derived macrophages cultured for 6 days in 5% human serum expressed PPAR{gamma} mRNA and protein by reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, PPAR{gamma} mRNA expression in U937 cells increased during phorbol 12-myristate 13 acetate-induced differentiation. Stimulation of PPAR{gamma} with troglitazone or 15-deoxy-{Delta}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{gamma} is present in macrophages in human atherosclerotic lesions and may regulate expression and activity of MMP-9, an enzyme implicated in plaque rupture. PPAR{gamma} is likely to be an important regulator of monocyte/macrophage function with relevance for human atherosclerotic disease.





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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]


Home page
JAMAHome page
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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J. Immunol.Home page
F. Bureau, C. Desmet, D. Melotte, F. Jaspar, C. Volanti, A. Vanderplasschen, P.-P. Pastoret, J. Piette, and P. Lekeux
A Proinflammatory Role for the Cyclopentenone Prostaglandins at Low Micromolar Concentrations: Oxidative Stress-Induced Extracellular Signal-Regulated Kinase Activation Without NF-{kappa}B Inhibition
J. Immunol., May 15, 2002; 168(10): 5318 - 5325.
[Abstract] [Full Text] [PDF]


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CirculationHome page
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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Mol. Pharmacol.Home page
S. Cuzzocrea, N. S. Wayman, E. Mazzon, L. Dugo, R. Di Paola, I. Serraino, D. Britti, P. K. Chatterjee, A. P. Caputi, and C. Thiemermann
The Cyclopentenone Prostaglandin 15-Deoxy-Delta 12,14-Prostaglandin J2 Attenuates the Development of Acute and Chronic Inflammation
Mol. Pharmacol., May 1, 2002; 61(5): 997 - 1007.
[Abstract] [Full Text] [PDF]


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Arterioscler. Thromb. Vasc. Bio.Home page
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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Biol. Reprod.Home page
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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Mol. Cell. Biol.Home page
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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J. Biol. Chem.Home page
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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Circ. Res.Home page
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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J. Clin. Endocrinol. Metab.Home page
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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J. Leukoc. Biol.Home page
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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Circ. Res.Home page
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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Circ. Res.Home page
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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Ann Rheum DisHome page
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]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
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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EndocrinologyHome page
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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Am. J. Respir. Crit. Care Med.Home page
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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HeartHome page
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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CirculationHome page
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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J. Clin. Endocrinol. Metab.Home page
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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Circ. Res.Home page
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]


Home page
J. Clin. Endocrinol. Metab.Home page
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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Proc. Natl. Acad. Sci. USAHome page
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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Diabetes CareHome page
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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CirculationHome page
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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ANN INTERN MEDHome page
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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IOVSHome page
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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J. Immunol.Home page
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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HypertensionHome page
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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J. Histochem. Cytochem.Home page
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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CirculationHome page
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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Mol. Cell. Biol.Home page
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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J. Immunol.Home page
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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Arterioscler. Thromb. Vasc. Bio.Home page
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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