This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aikawa, M. Articles by Libby, P. Search for Related Content PubMed PubMed Citation Articles by Aikawa, M. Articles by Libby, P. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Dietary Fats Related Collections Animal models of human disease Growth factors/cytokines Coagulation and fibronolysis Lipid and lipoprotein metabolism

(Circulation. 1999;100:1215-1222.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Dietary Lipid Lowering Reduces Tissue Factor Expression in Rabbit Atheroma

Presented in part at the 71st Scientific Sessions of the American Heart Association (Dallas, Tex, November 8–11, 1998) and published in abstract form (Circulation. 1998;98[suppl I]:I-40).

Masanori Aikawa, MD, PhD; Sami J. Voglic; Seigo Sugiyama, MD, PhD; Elena Rabkin, MD, PhD; Mark B. Taubman, MD; John T. Fallon, MD, PhD; Peter Libby, MD

From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (M.A., S.J.V., S.S., E.R., P.L.), and the Departments of Medicine (M.B.T., J.T.F.) and Pathology (J.T.F.), Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY.

Correspondence to Masanori Aikawa, MD, PhD, Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 309, Boston, MA 02115. E-mail maikawa{at}bics.bwh.harvard.edu

Background—The mechanisms by which lipid lowering reduces the incidence of acute thrombotic complications of coronary atheroma in clinical trials remains unknown. Tissue factor (TF) overexpressed in atheroma may accelerate thrombus formation at the sites of plaque disruption. A cell surface cytokine CD40 ligand (CD40L) enhances TF expression in vitro.

Methods and Results—To test the hypothesis that lipid lowering reduces TF expression and activity, we produced atheroma in rabbit aortas by balloon injury and cholesterol feeding for 4 months (Baseline group, n=15), followed by either a chow diet (Low group, n=10) or a continued high-cholesterol diet for 16 months (High group, n=5). Immunolocalization of TF, CD40L, and its receptor CD40 was quantified by computer-assisted color image analysis. Macrophages in atheroma of the Baseline and High groups strongly expressed TF. Intimal smooth muscle cells and endothelial cells also contained immunoreactive TF. Regions of expression of CD40L and CD40 colocalized with TF. Protein expression of TF diminished substantially in the Low group in association with reduced expression of CD40L and CD40. In situ binding of TF to factors VIIa and X, detected by digoxigenin-labeled factors VIIa and X, colocalized with TF protein in atheroma and decreased after lipid lowering. We also determined reduced TF biological activity in the Low group by use of a chromogenic assay. The level of TF mRNA detected by reverse transcription–polymerase chain reaction also decreased after lipid lowering.

Conclusions—These results suggest decreased expression and activity of TF as a novel mechanism of reduced incidence of thrombotic complications of atherosclerosis by lipid lowering.

Key Words: atherosclerosis • thrombosis • hypercholesterolemia • coagulation • macrophages

This article has been cited by other articles:

				P. Libby Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis J. Lipid Res., April 1, 2009; 50(Supplement): S352 - S357. [Abstract] [Full Text] [PDF]

				D. Steinberg, C. K. Glass, and J. L. Witztum Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia Circulation, August 5, 2008; 118(6): 672 - 677. [Full Text] [PDF]

				M. Levi and E. Stroes Targeting the prevention of plaque rupture as a new strategy for prevention of acute arterial cardiovascular events Cardiovasc Res, June 1, 2008; 78(3): 407 - 408. [Full Text] [PDF]

				T. W. Rice and A. B. Lumsden Optimal Medical Management of Peripheral Arterial Disease Vascular and Endovascular Surgery, August 1, 2006; 40(4): 312 - 327. [Abstract] [PDF]

				E. D. MacDougall, F. Kramer, P. Polinsky, S. Barnhart, B. Askari, F. Johansson, R. Varon, M. E. Rosenfeld, K. Oka, L. Chan, et al. Aggressive Very Low-Density Lipoprotein (VLDL) and LDL Lowering by Gene Transfer of the VLDL Receptor Combined with a Low-Fat Diet Regimen Induces Regression and Reduces Macrophage Content in Advanced Atherosclerotic Lesions in LDL Receptor-Deficient Mice Am. J. Pathol., June 1, 2006; 168(6): 2064 - 2073. [Abstract] [Full Text] [PDF]

				R. E. Tilley, B. Pedersen, R. Pawlinski, Y. Sato, J. H. Erlich, Y. Shen, S. Day, Y. Huang, D. T. Eitzman, W. A. Boisvert, et al. Atherosclerosis in Mice Is Not Affected by a Reduction in Tissue Factor Expression Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 555 - 562. [Abstract] [Full Text] [PDF]

				P. Libby Inflammation and cardiovascular disease mechanisms Am. J. Clinical Nutrition, February 1, 2006; 83(2): 456S - 460S. [Abstract] [Full Text] [PDF]

				S. K. Mandal, A. Iakhiaev, U. R. Pendurthi, and L. V. M. Rao Acute cholesterol depletion impairs functional expression of tissue factor in fibroblasts: modulation of tissue factor activity by membrane cholesterol Blood, January 1, 2005; 105(1): 153 - 160. [Abstract] [Full Text] [PDF]

				G. K. Hansson Glimpse of the Secret Life of the Plaque Arterioscler Thromb Vasc Biol, December 1, 2004; 24(12): 2203 - 2204. [Full Text] [PDF]

				E. Trogan, Z. A. Fayad, V. V. Itskovich, J.-G. S. Aguinaldo, V. Mani, J. T. Fallon, I. Chereshnev, and E. A. Fisher Serial Studies of Mouse Atherosclerosis by In Vivo Magnetic Resonance Imaging Detect Lesion Regression After Correction of Dyslipidemia Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1714 - 1719. [Abstract] [Full Text] [PDF]

				S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]

				W. Ni, S. Kitamoto, M. Ishibashi, M. Usui, S. Inoue, K.-i. Hiasa, Q. Zhao, K.-i. Nishida, A. Takeshita, and K. Egashira Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 534 - 539. [Abstract] [Full Text]

				T. Hayashi, D. Sumi, P. A.R Juliet, H. Matsui-Hirai, Y. Asai-Tanaka, H. Kano, A. Fukatsu, T. Tsunekawa, A. Miyazaki, A. Iguchi, et al. Gene transfer of endothelial NO synthase, but not eNOS, plus inducible NOS regressed atherosclerosis in rabbits Cardiovasc Res, February 1, 2004; 61(2): 339 - 351. [Abstract] [Full Text] [PDF]

				M. Pynn, K. Schafer, S. Konstantinides, and M. Halle Exercise Training Reduces Neointimal Growth and Stabilizes Vascular Lesions Developing After Injury in Apolipoprotein E-Deficient Mice Circulation, January 27, 2004; 109(3): 386 - 392. [Abstract] [Full Text] [PDF]

				E. Jeanpierre, T. Le Tourneau, I. Six, C. Zawadzki;, E. Van Belle, M. D. Ezekowitz, R. Bordet, S. Susen, B. Jude, and D. Corseaux Dietary Lipid Lowering Modifies Plaque Phenotype in Rabbit Atheroma After Angioplasty: A Potential Role of Tissue Factor Circulation, October 7, 2003; 108(14): 1740 - 1745. [Abstract] [Full Text] [PDF]

				D Tousoulis, G Davies, C Stefanadis, P Toutouzas, and J A Ambrose Inflammatory and thrombotic mechanisms in coronary atherosclerosis Heart, September 1, 2003; 89(9): 993 - 997. [Abstract] [Full Text] [PDF]

				F. Mulhaupt, C. M Matter, B. R Kwak, G. Pelli, N. R Veillard, F. Burger, P. Graber, T. F Luscher, and F. Mach Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells Cardiovasc Res, September 1, 2003; 59(3): 755 - 766. [Abstract] [Full Text] [PDF]

				A. J. Grau and C. Lichy Editorial Comment: Stroke and the CD40-CD40 Ligand System: At the Hinge Between Inflammation and Thrombosis Stroke, June 1, 2003; 34(6): 1417 - 1418. [Full Text] [PDF]

				K. Takayama, G. Garcia-Cardena, G. K. Sukhova, J. Comander, M. A. Gimbrone Jr., and P. Libby Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor J. Biol. Chem., November 8, 2002; 277(46): 44147 - 44154. [Abstract] [Full Text] [PDF]

				A. C. Sposito and M. J. Chapman Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1524 - 1534. [Abstract] [Full Text] [PDF]

				M. Aikawa, S. Sugiyama, C. C. Hill, S. J. Voglic, E. Rabkin, Y. Fukumoto, F. J. Schoen, J. L. Witztum, and P. Libby Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma Circulation, September 10, 2002; 106(11): 1390 - 1396. [Abstract] [Full Text] [PDF]

				U. Bavendiek, P. Libby, M. Kilbride, R. Reynolds, N. Mackman, and U. Schonbeck Induction of Tissue Factor Expression in Human Endothelial Cells by CD40 Ligand Is Mediated via Activator Protein 1, Nuclear Factor kappa B, and Egr-1 J. Biol. Chem., July 5, 2002; 277(28): 25032 - 25039. [Abstract] [Full Text] [PDF]

				R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]

				M. D. Rekhter How to evaluate plaque vulnerability in animal models of atherosclerosis? Cardiovasc Res, April 1, 2002; 54(1): 36 - 41. [Abstract] [Full Text] [PDF]

				A. H.M Moons, M. Levi, and R. J.G Peters Tissue factor and coronary artery disease Cardiovasc Res, February 1, 2002; 53(2): 313 - 325. [Abstract] [Full Text] [PDF]

				U. Schonbeck and P. Libby CD40 Signaling and Plaque Instability Circ. Res., December 7, 2001; 89(12): 1092 - 1103. [Abstract] [Full Text] [PDF]

				M. T. Johnstone, R. M. Botnar, A. S. Perez, R. Stewart, W. C. Quist, J. A. Hamilton, and W. J. Manning In Vivo Magnetic Resonance Imaging of Experimental Thrombosis in a Rabbit Model Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1556 - 1560. [Abstract] [Full Text] [PDF]

				P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]

				M. Aikawa and P. Libby Vascular inflammation and activation: new targets for lipid lowering Eur. Heart J. Suppl., May 1, 2001; 3(suppl_B): B3 - B11. [Abstract] [PDF]

				Y. Fukumoto, P. Libby, E. Rabkin, C. C. Hill, M. Enomoto, Y. Hirouchi, M. Shiomi, and M. Aikawa Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits Circulation, February 20, 2001; 103(7): 993 - 999. [Abstract] [Full Text] [PDF]

				M. Aikawa, E. Rabkin, S. Sugiyama, S. J. Voglic, Y. Fukumoto, Y. Furukawa, M. Shiomi, F. J. Schoen, and P. Libby An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro Circulation, January 16, 2001; 103(2): 276 - 283. [Abstract] [Full Text] [PDF]

				M. S. Penn, M.-Z. Cui, A. L. Winokur, J. Bethea, T. A. Hamilton, P. E. DiCorleto, and G. M. Chisolm Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation Blood, November 1, 2000; 96(9): 3056 - 3063. [Abstract] [Full Text] [PDF]

				M. M. Kockx, C. Seye, G. R. Y. De Meyer, M. W. M. Knaapen, M. Aikawa, S. J. Voglic, S. Sugiyama, E. Rabkin, P. Libby, M. B. Taubman, et al. Decreased Apoptosis and Tissue Factor Expression After Lipid Lowering Response Circulation, September 26, 2000; 102 (13): e99 - e99. [Full Text] [PDF]

				S. Matetzky, S. Tani, S. Kangavari, P. Dimayuga, J. Yano, H. Xu, K.-Y. Chyu, M. C. Fishbein, P. K. Shah, and B. Cercek Smoking Increases Tissue Factor Expression in Atherosclerotic Plaques : Implications for Plaque Thrombogenicity Circulation, August 8, 2000; 102(6): 602 - 604. [Abstract] [Full Text] [PDF]

				M. J Davies CORONARY DISEASE: The pathophysiology of acute coronary syndromes Heart, March 1, 2000; 83(3): 361 - 366. [Full Text]

				R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]