(Circulation. 2001;103:1778.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Acyl-CoA:Cholesterol Acyltransferase Inhibitor Avasimibe Reduces Atherosclerosis in Addition to Its Cholesterol-Lowering Effect in ApoE*3-Leiden Mice
From Gaubius Laboratory, TNO-PG (D.J.M.D., E.H.O., W.v.D., H.v.d.B., E.C.M.d.W., L.M.H., H.M.G.P.); the Department of Human Genetics, Leiden University Medical Centre (M.J.J.G.); and the Department of Cardiology, Leiden University Medical Centre (A.v.d.L., J.W.J.), Leiden, the Netherlands.
Correspondence to Dr H.M.G. Princen, Gaubius Laboratory, TNO-PG, PO Box 2215, 2301 CE Leiden, the Netherlands. E-mail jmg.princen{at}pg.tno.nl
Background—The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice.
Methods and Results—Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (HC) diet; 1 group received 0.01% (wt/wt) avasimibe mixed into the diet. The HC diet resulted in a plasma cholesterol concentration of 18.7±2.6 mmol/L. Addition of avasimibe lowered plasma cholesterol by 56% to 8.1±1.2 mmol/L, caused mainly by a reduction of and composition change in VLDL and LDL. In a separate low-cholesterol (LC) control group, plasma cholesterol was titrated to a level comparable to that of the avasimibe group (10.3±1.4 mmol/L) by lowering the amount of dietary cholesterol. After 22 weeks of intervention, atherosclerosis in the aortic root area was quantified. Treatment with avasimibe resulted in a 92% reduction of lesion area compared with the HC control group. Compared with the LC control, avasimibe reduced lesion area by 78%. After correction for the slight difference in cholesterol exposure between the LC control and avasimibe groups, the effect of avasimibe on lesion area (73% reduction) remained highly significant. In addition, monocyte adherence to the endothelium, free cholesterol accumulation, and lesion severity were reduced by avasimibe treatment.
Conclusions—Treatment with avasimibe potently lowered plasma cholesterol levels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adherence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefore a reduced risk of plaque rupture.
Key Words: atherosclerosis • inhibitors • lipoproteins • cell adhesion molecules
This article has been cited by other articles:
 |
|
 |
|
  M. C. Meuwese, E. de Groot, R. Duivenvoorden, M. D. Trip, L. Ose, F. J. Maritz, D. C. G. Basart, J. J. P. Kastelein, R. Habib, M. H. Davidson, et al. ACAT Inhibition and Progression of Carotid Atherosclerosis in Patients With Familial Hypercholesterolemia: The CAPTIVATE Randomized Trial JAMA, March 18, 2009; 301(11): 1131 - 1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W.A. van der Hoorn, W. de Haan, J. F.P. Berbee, L. M. Havekes, J. W. Jukema, P. C.N. Rensen, and H. M.G. Princen Niacin Increases HDL by Reducing Hepatic Expression and Plasma Levels of Cholesteryl Ester Transfer Protein in APOE*3Leiden.CETP Mice Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 2016 - 2022. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fujiwara, N. Kiyota, M. Hori, S. Matsushita, Y. Iijima, K. Aoki, D. Shibata, M. Takeya, T. Ikeda, T. Nohara, et al. Esculeogenin A, a New Tomato Sapogenol, Ameliorates Hyperlipidemia and Atherosclerosis in ApoE-Deficient Mice by Inhibiting ACAT Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2400 - 2406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zadelaar, R. Kleemann, L. Verschuren, J. de Vries-Van der Weij, J. van der Hoorn, H. M. Princen, and T. Kooistra Mouse Models for Atherosclerosis and Pharmaceutical Modifiers Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1706 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cheng, D. Tempel, R. van Haperen, A. van der Baan, F. Grosveld, M. J.A.P. Daemen, R. Krams, and R. de Crom Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress Circulation, June 13, 2006; 113(23): 2744 - 2753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. T. Dalen, S. M. Ulven, B. M. Arntsen, K. Solaas, and H. I. Nebb PPAR{alpha} activators and fasting induce the expression of adipose differentiation-related protein in liver J. Lipid Res., May 1, 2006; 47(5): 931 - 943. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Nissen, E. M. Tuzcu, H. B. Brewer, I. Sipahi, S. J. Nicholls, P. Ganz, P. Schoenhagen, D. D. Waters, C. J. Pepine, T. D. Crowe, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N. Engl. J. Med., March 23, 2006; 354(12): 1253 - 1263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Tam, J. B. Ancsin, R. Tan, and R. Kisilevsky Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE-/- mice J. Lipid Res., October 1, 2005; 46(10): 2091 - 2101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Moselewski, C. J. O'Donnell, S. Achenbach, M. Ferencik, J. Massaro, A. Nguyen, R. C. Cury, S. Abbara, I.-K. Jang, T. J. Brady, et al. Calcium Concentration of Individual Coronary Calcified Plaques as Measured by Multidetector Row Computed Tomography Circulation, June 21, 2005; 111(24): 3236 - 3241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Vidal, S. Hernandez-Vallejo, T. Pauquai, O. Texier, M. Rousset, J. Chambaz, S. Demignot, and J.-M. Lacorte Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes J. Lipid Res., February 1, 2005; 46(2): 258 - 268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Verschuren, R. Kleemann, E. H. Offerman, A. J. Szalai, S. J. Emeis, H. M. G. Princen, and T. Kooistra Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3-Leiden Transgenic Mice Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 161 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Tardif, J. Gregoire, P. L. L'Allier, T. J. Anderson, O. Bertrand, F. Reeves, L. M. Title, F. Alfonso, E. Schampaert, A. Hassan, et al. Effects of the Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor Avasimibe on Human Atherosclerotic Lesions Circulation, November 23, 2004; 110(21): 3372 - 3377. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Meir and E. Leitersdorf Atherosclerosis in the Apolipoprotein E-Deficient Mouse: A Decade of Progress Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 1006 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. S. Espirito Santo, N. M. M. Pires, L. S. M. Boesten, G. Gerritsen, N. Bovenschen, K. W. van Dijk, J. W. Jukema, H. M. G. Princen, A. Bensadoun, W.-P. Li, et al. Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol Blood, May 15, 2004; 103(10): 3777 - 3782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lie, R. de Crom, T. van Gent, R. van Haperen, L. Scheek, F. Sadeghi-Niaraki, and A. van Tol Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins J. Lipid Res., May 1, 2004; 45(5): 805 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. de Medina, B. L. Payre, J. Bernad, I. Bosser, B. Pipy, S. Silvente-Poirot, G. Favre, J.-C. Faye, and M. Poirot Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 1165 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Namatame, H. Tomoda, S. Ishibashi, and S. Omura Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages PNAS, January 20, 2004; 101(3): 737 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kleemann, H. M.G. Princen, J. J. Emeis, J. W. Jukema, R. D. Fontijn, A. J.G. Horrevoets, T. Kooistra, and L. M. Havekes Rosuvastatin Reduces Atherosclerosis Development Beyond and Independent of Its Plasma Cholesterol-Lowering Effect in APOE*3-Leiden Transgenic Mice: Evidence for Antiinflammatory Effects of Rosuvastatin Circulation, September 16, 2003; 108(11): 1368 - 1374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Willner, B. Tow, K. K. Buhman, M. Wilson, D. A. Sanan, L. L. Rudel, and R. V. Farese Jr. Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice PNAS, February 4, 2003; 100(3): 1262 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Buhman, H. C. Chen, and R. V. Farese Jr. The Enzymes of Neutral Lipid Synthesis J. Biol. Chem., October 26, 2001; 276(44): 40369 - 40372. [Full Text] [PDF]
|
|