Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:365-371
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Troglitazone Inhibits Formation of Early Atherosclerotic Lesions in Diabetic and Nondiabetic Low Density Lipoprotein Receptor–Deficient Mice
From the Division of Endocrinology, Diabetes, and Hypertension (A.R.C., W.P.M., U.K., S.J., S.W., G.N., W.A.H., R.E.L.), Department of Medicine, UCLA School of Medicine, Los Angeles, Calif; the Molecular Biology Institute (W.A.H., R.E.L.), Los Angeles, Calif; the Department of Medicine/Cardiology (U.K.), Virchow-Klinikum, Humboldt University, and the German Heart Institute (U.K.), Berlin, Germany; and the Department of Medicine (W.P.), UCSD, La Jolla, Calif.
Correspondence to Ronald E. Law, PhD, University of California, Los Angeles, Division of Endocrinology, Diabetes, and Hypertension, 900 Veteran Ave, Suite 24-130, Box 957073, Los Angeles, CA 90095. E-mail rlaw{at}mednet.ucla.edu
Abstract—Peroxisome
proliferator–activated receptor-
(PPAR) is a
ligand-activated nuclear receptor expressed in all of the major
cell types found in atherosclerotic lesions:
monocytes/macrophages, endothelial cells, and
smooth muscle cells. In vitro, PPAR ligands inhibit cell
proliferation and migration, 2 processes critical for vascular lesion
formation. In contrast to these putative antiatherogenic activities,
PPAR has been shown in vitro to upregulate the CD36 scavenger
receptor, which could promote foam cell formation. Thus, it is unclear
what impact PPAR activation will have on the development and
progression of atherosclerosis. This issue is important
because thiazolidinediones, which are ligands for PPAR, have
recently been approved for the treatment of type 2 diabetes, a state of
accelerated atherosclerosis. We report herein that the
PPAR ligand, troglitazone, inhibited lesion formation in male low
density lipoprotein receptor–deficient mice fed either a high-fat
diet, which also induces type 2 diabetes, or a high-fructose diet.
Troglitazone decreased the accumulation of macrophages in
intimal xanthomas, consistent with our in vitro observation
that troglitazone and another thiazolidinedione, rosiglitazone,
inhibited monocyte chemoattractant protein-1–directed
transendothelial migration of monocytes. Although
troglitazone had some beneficial effects on metabolic risk
factors (in particular, a reduction of insulin levels in the diabetic
model), none of the systemic cardiovascular risk
factors was consistently improved in either model. These
observations suggest that the inhibition of early atherosclerotic
lesion formation by troglitazone may result, at least in part, from
direct effects of PPAR activation in the artery
wall.
Key Words: atherosclerosis • diabetes mellitus • pharmacology
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N. Satoh, Y. Ogawa, T. Usui, T. Tagami, S. Kono, H. Uesugi, H. Sugiyama, A. Sugawara, K. Yamada, A. Shimatsu, et al. Antiatherogenic Effect of Pioglitazone in Type 2 Diabetic Patients Irrespective of the Responsiveness to Its Antidiabetic Effect Diabetes Care, September 1, 2003; 26(9): 2493 - 2499. [Abstract] [Full Text] [PDF]
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C. J. Lyon, R. E. Law, and W. A. Hsueh Minireview: Adiposity, Inflammation, and Atherogenesis Endocrinology, June 1, 2003; 144(6): 2195 - 2200. [Abstract] [Full Text] [PDF]
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C.-H. Lee, P. Olson, and R. M. Evans Minireview: Lipid Metabolism, Metabolic Diseases, and Peroxisome Proliferator-Activated Receptors Endocrinology, June 1, 2003; 144(6): 2201 - 2207. [Abstract] [Full Text] [PDF]
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S. T. de Dios, D. Bruemmer, R. J. Dilley, M. E. Ivey, G. L.R. Jennings, R. E. Law, and P. J. Little Inhibitory Activity of Clinical Thiazolidinedione Peroxisome Proliferator Activating Receptor-{gamma} Ligands Toward Internal Mammary Artery, Radial Artery, and Saphenous Vein Smooth Muscle Cell Proliferation Circulation, May 27, 2003; 107(20): 2548 - 2550. [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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K. M. Hannan, R. J. Dilley, S. T. de Dios, and P. J. Little Troglitazone Stimulates Repair of the Endothelium and Inhibits Neointimal Formation in Denuded Rat Aorta Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 762 - 768. [Abstract] [Full Text] [PDF]
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C.A. Argmann, C.G. Sawyez, C.J. McNeil, R.A. Hegele, and M.W. Huff Activation of Peroxisome Proliferator-Activated Receptor Gamma and Retinoid X Receptor Results in Net Depletion of Cellular Cholesteryl Esters in Macrophages Exposed to Oxidized Lipoproteins Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 475 - 482. [Abstract] [Full Text] [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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D. S. Calnek, L. Mazzella, S. Roser, J. Roman, and C. M. Hart Peroxisome Proliferator-Activated Receptor {gamma} Ligands Increase Release of Nitric Oxide From Endothelial Cells Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 52 - 57. [Abstract] [Full Text] [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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Y. Kako, M. Masse, L.-S. Huang, A. R. Tall, and I. J. Goldberg Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice J. Lipid Res., June 1, 2002; 43(6): 872 - 877. [Abstract] [Full Text] [PDF]
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S. B. Joseph, E. McKilligin, L. Pei, M. A. Watson, A. R. Collins, B. A. Laffitte, M. Chen, G. Noh, J. Goodman, G. N. Hagger, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice PNAS, May 28, 2002; 99(11): 7604 - 7609. [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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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. Walczak and P. Tontonoz PPARadigms and PPARadoxes: expanding roles for PPAR{gamma} in the control of lipid metabolism J. Lipid Res., February 1, 2002; 43(2): 177 - 186. [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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H. Vosper, L. Patel, T. L. Graham, G. A. Khoudoli, A. Hill, C. H. Macphee, I. Pinto, S. A. Smith, K. E. Suckling, C. R. Wolf, et al. The Peroxisome Proliferator-activated Receptor delta Promotes Lipid Accumulation in Human Macrophages J. Biol. Chem., November 16, 2001; 276(47): 44258 - 44265. [Abstract] [Full Text] [PDF]
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C. K. Glass Antiatherogenic Effects of Thiazolidinediones? Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 295 - 296. [Full Text] [PDF]
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