Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:372-377
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Troglitazone Inhibits Atherosclerosis in Apolipoprotein E–Knockout Mice
Pleiotropic Effects on CD36 Expression and HDL
From the Departments of Metabolic Diseases (Z.C., S.I., S.P., J.-i.O., T.G., T.K., Y.T., H.O., N. Yahagi, Y.I., F.S., K.O., K.H., H.S., N. Yamada) and Cardiovascular Medicine (R.N.), Faculty of Medicine, University of Tokyo, Tokyo, Japan. Dr Yamada and Dr Shimano are presently at the Metabolism, Endocrinology and Atherosclerosis Section, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Correspondence to Shun Ishibashi, MD, PhD, Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail ishibash-tky{at}umin.u-tokyo.ac.jp
Abstract—Atherosclerotic
coronary heart disease is a common complication of the insulin
resistance syndrome that can occur with or without diabetes mellitus.
Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic
agents, can modulate the development of atherosclerosis
not only by changing the systemic metabolic conditions
associated with insulin resistance but also by exerting direct effects
on vascular wall cells that express peroxisome
proliferator–activated receptor-
(PPAR-), a nuclear
receptor for TZDs. Here we show that troglitazone, a TZD, significantly
inhibited fatty streak lesion formation in apolipoprotein E–knockout
mice fed a high-fat diet (en face aortic surface lesion areas were
6.9±2.5% vs 12.7±4.7%,
P<0.05; cross-sectional lesion
areas were 191 974±102 911 µm2 vs
351 738±175 597 µm2,
P<0.05; n=10). Troglitazone
attenuated hyperinsulinemic hyperglycemia and increased
high density lipoprotein cholesterol levels. In the aorta,
troglitazone markedly increased the mRNA levels of CD36, a scavenger
receptor for oxidized low density lipoprotein, presumably by
upregulating its expression, at least in part, in the
macrophage foam cells. These results indicate that troglitazone
potently inhibits fatty streak lesion formation by modulating both
metabolic extracellular environments and
arterial wall cell functions.
Key Words: atherosclerosis • thiazolidinediones • lipoproteins • CD36 • peroxisome proliferator–activated receptor
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J. Han, D. P. Hajjar, X. Zhou, A. M. Gotto Jr., and A. C. Nicholson Regulation of Peroxisome Proliferator-activated Receptor-gamma -mediated Gene Expression. A NEW MECHANISM OF ACTION FOR HIGH DENSITY LIPOPROTEIN J. Biol. Chem., June 21, 2002; 277(26): 23582 - 23586. [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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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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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. 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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L. L. Demer Adipose Rex: Fat and Fats That Rule Differentiation Circ. Res., February 22, 2002; 90(3): 241 - 243. [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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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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 B. Staels The clinical significance of PPAR{alpha} and {gamma} agonism The British Journal of Diabetes & Vascular Disease, January 1, 2002; 2(1_suppl): S28 - S31. [Abstract] [PDF]
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H. R. Davis Jr, D. S. Compton, L. Hoos, and G. Tetzloff Ezetimibe, a Potent Cholesterol Absorption Inhibitor, Inhibits the Development of Atherosclerosis in ApoE Knockout Mice Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2032 - 2038. [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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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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