© 1998 American Heart Association, Inc.
Original Contributions |
Peroxisome Proliferator-Activated Receptor Gamma Activators Inhibit Gene Expression and Migration in Human Vascular Smooth Muscle Cells
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School (N.M., U.S., P.L., J.P.), Boston, Mass, and the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and the Department of Genetics, University of Pennsylvania School of Medicine (M.A.L.), Philadelphia, Pa.
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}bustoff.bwh.harvard.edu
Abstract—Migration of vascular
smooth muscle cells (VSMCs) plays an important role in atherogenesis
and restenosis after arterial interventions. The
expression of matrix metalloproteinases (MMPs), particularly MMP-9,
contributes to VSMC migration. This process requires degradation of
basal laminae and other components of the arterial
extracellular matrix. Peroxisome proliferator-activated
receptors (PPARs), members of the nuclear receptor family, regulate
gene expression after activation by various ligands. Recent studies
have suggested opposing effects of PPAR gamma (PPAR
) activation on
atherogenesis. The present study tested the hypotheses that human
VSMCs express PPAR alpha (PPAR
) and PPAR and that PPAR agonists
in VSMCs modulate MMP-9 expression and activity, as well as VSMC
migration. Human VSMCs expressed PPAR and PPAR mRNA and protein.
Treatment of VSMCs with the PPAR ligands troglitazone and the
naturally occurring
15-deoxy-
12,14-prostaglandin J2
(15d-PGJ2) decreased phorbol 12-myristate
13-acetate–induced MMP-9 mRNA and protein levels, as well as MMP-9
gelatinolytic activity in the supernatants in a
concentration-dependent manner. Six different PPAR
activators lacked such effects. Addition of
prostaglandin F2, known to limit PPAR
activity, diminished the MMP-9 inhibition seen with either troglitazone
or 15d-PGJ2, further implicating PPAR in these effects.
Finally, troglitazone and 15d-PGJ2 inhibited the
platelet-derived growth factor-BB–induced migration of
VSMCs in vitro in a concentration-dependent manner. PPAR activation
may regulate VSMC migration and expression and activity of MMP-9. Thus,
PPAR activation in VSMCs, via the antidiabetic agent troglitazone or
naturally occurring ligands, may act to counterbalance other
potentially proatherosclerotic PPAR effects.
Key Words: gene expression • vascular smooth muscle cell • migration • peroxisome proliferator-activated receptor gamma • troglitazone
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Y. Taba, M. Miyagi, Y. Miwa, H. Inoue, F. Takahashi-Yanaga, S. Morimoto, and T. Sasaguri 15-Deoxy-{Delta}12,14-prostaglandin J2 and laminar fluid shear stress stabilize c-IAP1 in vascular endothelial cells Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H38 - H46. [Abstract] [Full Text] [PDF]
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 K.-H. Mak and D. P. Faxon Clinical studies on coronary revascularization in patients with type 2 diabetes Eur. Heart J., June 2, 2003; 24(12): 1087 - 1103. [Abstract] [Full Text] [PDF]
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 D. Bruemmer, F. Yin, J. Liu, J. P. Berger, T. Kiyono, J. Chen, E. Fleck, A. J. Van Herle, B. M. Forman, and R. E. Law Peroxisome Proliferator-Activated Receptor {gamma} Inhibits Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells Mol. Endocrinol., June 1, 2003; 17(6): 1005 - 1018. [Abstract] [Full Text] [PDF]
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 J. S. Welch, M. Ricote, T. E. Akiyama, F. J. Gonzalez, and C. K. Glass PPAR{gamma} and PPAR{delta} negatively regulate specific subsets of lipopolysaccharide and IFN-{gamma} target genes in macrophages PNAS, May 27, 2003; 100(11): 6712 - 6717. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Inflammation and Insulin Resistance Diabetes Care, May 1, 2003; 26(5): 1619 - 1623. [Full Text] [PDF]
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 F. Zangeneh, Y. C. Kudva, and A. Basu Insulin Sensitizers Mayo Clin. Proc., April 1, 2003; 78(4): 471 - 479. [Abstract] [PDF]
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N. Marx, J. Froehlich, L. Siam, J. Ittner, G. Wierse, A. Schmidt, H. Scharnagl, V. Hombach, and W. Koenig Antidiabetic PPAR{gamma}-Activator Rosiglitazone Reduces MMP-9 Serum Levels in Type 2 Diabetic Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 283 - 288. [Abstract] [Full Text] [PDF]
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J. Martinez-Gonzalez, J. Rius, A. Castello, C. Cases-Langhoff, and L. Badimon Neuron-Derived Orphan Receptor-1 (NOR-1) Modulates Vascular Smooth Muscle Cell Proliferation Circ. Res., January 10, 2003; 92(1): 96 - 103. [Abstract] [Full Text] [PDF]
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M. Iglarz, R. M. Touyz, F. Amiri, M.-F. Lavoie, Q. N. Diep, and E. L. Schiffrin Effect of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} Activators on Vascular Remodeling in Endothelin-Dependent Hypertension Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 45 - 51. [Abstract] [Full Text] [PDF]
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T. Shiomi, H. Tsutsui, S. Hayashidani, N. Suematsu, M. Ikeuchi, J. Wen, M. Ishibashi, T. Kubota, K. Egashira, and A. Takeshita Pioglitazone, a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction Circulation, December 10, 2002; 106(24): 3126 - 3132. [Abstract] [Full Text] [PDF]
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U. Kintscher, C. Lyon, S. Wakino, D. Bruemmer, X. Feng, S. Goetze, K. Graf, A. Moustakas, B. Staels, E. Fleck, et al. PPAR{alpha} Inhibits TGF-{beta}-Induced {beta}5 Integrin Transcription in Vascular Smooth Muscle Cells by Interacting With Smad4 Circ. Res., November 29, 2002; 91 (11): e35 - e44. [Abstract] [Full Text] [PDF]
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Z.-W. Hu, R. Kerb, X.-Y. Shi, T. Wei-Lavery, and B. B. Hoffman Angiotensin II Increases Expression of Cyclooxygenase-2: Implications for the Function of Vascular Smooth Muscle Cells J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 563 - 573. [Abstract] [Full Text] [PDF]
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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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M. Ishibashi, K. Egashira, K.-i. Hiasa, S. Inoue, W. Ni, Q. Zhao, M. Usui, S. Kitamoto, T. Ichiki, and A. Takeshita Antiinflammatory and Antiarteriosclerotic Effects of Pioglitazone Hypertension, November 1, 2002; 40(5): 687 - 693. [Abstract] [Full Text] [PDF]
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S. Goetze, A. Bungenstock, C. Czupalla, F. Eilers, P. Stawowy, U. Kintscher, C. Spencer-Hansch, K. Graf, B. Nurnberg, R. E. Law, et al. Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPAR{gamma}-Ligands Hypertension, November 1, 2002; 40(5): 748 - 754. [Abstract] [Full Text] [PDF]
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Y. Sakomura, H. Nagashima, Y. Aoka, K. Uto, A. Sakuta, S. Aomi, H. Kurosawa, T. Nishikawa, and H. Kasanuki Expression of Peroxisome Proliferator-Activated Receptor-{gamma} in Vascular Smooth Muscle Cells Is Upregulated in Cystic Medial Degeneration of Annuloaortic Ectasia in Marfan Syndrome Circulation, September 24, 2002; 106(12_suppl_1): I-259 - I-263. [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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D. Bishop-Bailey, T. Hla, and T. D. Warner Intimal Smooth Muscle Cells as a Target for Peroxisome Proliferator-Activated Receptor-{gamma} Ligand Therapy Circ. Res., August 9, 2002; 91(3): 210 - 217. [Abstract] [Full Text] [PDF]
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S. M. Haffner, A. S. Greenberg, W. M. Weston, H. Chen, K. Williams, and M. I. Freed Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus Circulation, August 6, 2002; 106(6): 679 - 684. [Abstract] [Full Text] [PDF]
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 P. A. Watson, C. Vinson, A. Nesterova, and J. E.-B. Reusch Content and Activity of cAMP Response Element-Binding Protein Regulate Platelet-Derived Growth Factor Receptor-{alpha} Content in Vascular Smooth Muscles Endocrinology, August 1, 2002; 143(8): 2922 - 2929. [Abstract] [Full Text] [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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 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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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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A. Sugawara, A. Uruno, M. Kudo, Y. Ikeda, K. Sato, Y. Taniyama, S. Ito, and K. Takeuchi Transcription Suppression of Thromboxane Receptor Gene by Peroxisome Proliferator-activated Receptor-gamma via an Interaction with Sp1 in Vascular Smooth Muscle Cells J. Biol. Chem., March 15, 2002; 277(12): 9676 - 9683. [Abstract] [Full Text] [PDF]
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T. Shibata, M. Kondo, T. Osawa, N. Shibata, M. Kobayashi, and K. Uchida 15-Deoxy-Delta 12,14-prostaglandin J2. A PROSTAGLANDIN D2 METABOLITE GENERATED DURING INFLAMMATORY PROCESSES J. Biol. Chem., March 15, 2002; 277(12): 10459 - 10466. [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. Diab, C. Deng, J. D. Smith, R. Z. Hussain, B. Phanavanh, A. E. Lovett-Racke, P. D. Drew, and M. K. Racke Peroxisome Proliferator-Activated Receptor-{gamma} Agonist 15-Deoxy-{Delta}12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2002; 168(5): 2508 - 2515. [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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S. Arima, K. Kohagura, K. Takeuchi, Y. Taniyama, A. Sugawara, Y. Ikeda, M. Abe, K. Omata, and S. Ito Biphasic Vasodilator Action of Troglitazone on the Renal Microcirculation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 342 - 349. [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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M. Fu, J. Zhang, X. Zhu, D. E. Myles, T. M. Willson, X. Liu, and Y. E. Chen Peroxisome Proliferator-activated Receptor gamma Inhibits Transforming Growth Factor beta -induced Connective Tissue Growth Factor Expression in Human Aortic Smooth Muscle Cells by Interfering with Smad3 J. Biol. Chem., November 30, 2001; 276(49): 45888 - 45894. [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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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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