(Circulation. 2000;101:235.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Modulation of Vascular Inflammation In Vitro and In Vivo by Peroxisome Proliferator–Activated Receptor-
Activators
From the Department of Internal Medicine (V.P., H.D.W., J.T.W., E.T.H.Y.) and Institute of Molecular Medicine for the Prevention of Human Diseases (E.T.H.Y.), University of Texas Health Science Center, and Texas Heart Institute (V.P., J.T.W., E.T.H.Y.), St Luke’s Episcopal Hospital, Houston.
Correspondence to Edward T.H. Yeh, MD, Department of Internal Medicine, 6431 Fannin, Suite 4200, UT-Houston HSC, Houston, TX 77030.
Background—Peroxisome
proliferator–activated receptor-
(PPAR) is expressed in
atherosclerotic plaques and in endothelial cells. The
possible effects of PPAR activators on
endothelial activation and inflammatory response within
the plaque are currently unknown.
Methods and Results—We tested the hypothesis that PPAR
activators inhibit vascular cell adhesion molecule (VCAM-1)
and intercellular adhesion molecule (ICAM-1) expression in cultured
endothelial cells (evaluated by flow cytometry) and
homing of monocyte/macrophages to atherosclerotic plaques in
vivo. In endothelial cells, the PPAR agonists
troglitazone at 100 µmol/L and
15-deoxy-
12,14-prostaglandin
J2 (15d-PGJ2) at 20 µmol/L markedly attenuated the
tumor necrosis factor–induced expression of VCAM-1 and ICAM-1. A
significant inhibition of VCAM-1 expression was also evident at 5 and
10 µmol/L 15d-PGJ2 and 20 µmol/L troglitazone. Expression
of E-selectin and PECAM-1 was not altered. To confirm the biological
relevance of these results, we assessed the effects of troglitazone on
monocyte/macrophage homing to atherosclerotic plaques in
apoE-deficient mice. A 7-day treatment with troglitazone (400 mg/kg)
significantly reduced monocyte/macrophage homing to
atherosclerotic plaques (236±77 versus 177±43 macrophages,
P=0.03); an even more striking inhibition was found at
3200 mg/kg troglitazone (344±76 versus 172±83 macrophages,
P=0.005).
Conclusions—PPAR activators inhibit expression of
VCAM-1 and ICAM-1 in activated endothelial
cells and significantly reduce monocyte/macrophage homing to
atherosclerotic plaques. These findings suggest that PPAR
activators, currently used in treatment of type II
diabetes, may have beneficial effects in modulating inflammatory
response in atherosclerosis.
Key Words: cell adhesion molecules • receptors • atherosclerosis
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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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N. Wang, L. Verna, N.-G. Chen, J. Chen, H. Li, B. M. Forman, and M. B. Stemerman Constitutive Activation of Peroxisome Proliferator-activated Receptor-gamma Suppresses Pro-inflammatory Adhesion Molecules in Human Vascular Endothelial Cells J. Biol. Chem., September 6, 2002; 277(37): 34176 - 34181. [Abstract] [Full Text] [PDF]
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 S. Sethi, O. Ziouzenkova, H. Ni, D. D. Wagner, J. Plutzky, and T. N. Mayadas Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPARalpha Blood, July 30, 2002; 100(4): 1340 - 1346. [Abstract] [Full Text] [PDF]
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D. L. Bhatt and E. J. Topol Need to Test the Arterial Inflammation Hypothesis Circulation, July 2, 2002; 106(1): 136 - 140. [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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 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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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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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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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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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. 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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A.-L. Levonen, D. A. Dickinson, D. R. Moellering, R. T. Mulcahy, H. J. Forman, and V. M. Darley-Usmar Biphasic Effects of 15-Deoxy-{Delta}12,14-Prostaglandin J2 on Glutathione Induction and Apoptosis in Human Endothelial Cells Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1846 - 1851. [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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 S. Narravula and S. P. Colgan Hypoxia-Inducible Factor 1-Mediated Inhibition of Peroxisome Proliferator-Activated Receptor {{alpha}} Expression During Hypoxia J. Immunol., June 15, 2001; 166(12): 7543 - 7548. [Abstract] [Full Text] [PDF]
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L. Serghides and K. C. Kain Peroxisome Proliferator-Activated Receptor {{gamma}}-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis of Plasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-{{alpha}} Secretion by Monocytes/Macrophages J. Immunol., June 1, 2001; 166(11): 6742 - 6748. [Abstract] [Full Text] [PDF]
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V. Pasceri, J. Chang, J. T. Willerson, and E. T. H. Yeh Modulation of C-Reactive Protein-Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs Circulation, May 29, 2001; 103(21): 2531 - 2534. [Abstract] [Full Text] [PDF]
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 S. X. Cheng and T. Kupper A New Rexinoid for Cutaneous T-Cell Lymphoma Arch Dermatol, May 1, 2001; 137(5): 649 - 652. [Full Text] [PDF]
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 T. Murata, Y. Hata, T. Ishibashi, S. Kim, W. A. Hsueh, R. E. Law, and D. R. Hinton Response of Experimental Retinal Neovascularization to Thiazolidinediones Arch Ophthalmol, May 1, 2001; 119(5): 709 - 717. [Abstract] [Full Text] [PDF]
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A. R. Collins, W. P. Meehan, U. Kintscher, S. Jackson, S. Wakino, G. Noh, W. Palinski, W. A. Hsueh, and R. E. Law Troglitazone Inhibits Formation of Early Atherosclerotic Lesions in Diabetic and Nondiabetic Low Density Lipoprotein Receptor-Deficient Mice Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 365 - 371. [Abstract] [Full Text] [PDF]
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Z. Chen, S. Ishibashi, S. Perrey, J.-i. Osuga, T. Gotoda, T. Kitamine, Y. Tamura, H. Okazaki, N. Yahagi, Y. Iizuka, et al. Troglitazone Inhibits Atherosclerosis in Apolipoprotein E-Knockout Mice : Pleiotropic Effects on CD36 Expression and HDL Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 372 - 377. [Abstract] [Full Text] [PDF]
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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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C. S. Elangbam, R. D. Tyler, and R. M. Lightfoot Peroxisome Proliferator-activated Receptors in Atherosclerosis and Inflammation--An Update Toxicol Pathol, February 1, 2001; 29(2): 224 - 231. [Abstract] [PDF]
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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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V. Pasceri, J. T. Willerson, and E. T. H. Yeh Direct Proinflammatory Effect of C-Reactive Protein on Human Endothelial Cells Circulation, October 31, 2000; 102(18): 2165 - 2168. [Abstract] [Full Text] [PDF]
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T. Claudel, M. D. Leibowitz, C. Fievet, 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 27, 2001; 98(5): 2610 - 2615. [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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