This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 25/1/161    most recent 01.ATV.0000148866.29829.19v1 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 Verschuren, L. Articles by Kooistra, T. Search for Related Content PubMed PubMed Citation Articles by Verschuren, L. Articles by Kooistra, T. Related Collections Animal models of human disease Pathophysiology Genetically altered mice Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:161.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effect of Low Dose Atorvastatin Versus Diet-Induced Cholesterol Lowering on Atherosclerotic Lesion Progression and Inflammation in Apolipoprotein E*3–Leiden Transgenic Mice

Lars Verschuren; Robert Kleemann; Erik H. Offerman; Alexander J. Szalai; Sjef J. Emeis; Hans M. G. Princen; Teake Kooistra

From the Gaubius Laboratory (L.V., R.K., E.H.O., S.J.E., H.M.G.P., T.K.), TNO-Prevention and Health, Leiden and Leiden University Medical Center, Department of Surgery (L.V., R.K.), Leiden, The Netherlands; and the University of Alabama at Birmingham, Department of Medicine (A.J.S.), Birmingham, Ala.

Correspondence to Robert Kleemann, Gaubius Laboratory, TNO-Prevention and Health, PO Box 2215, 2301 CE Leiden, The Netherlands. E-mail R.Kleemann{at}pg.tno.nl

Objective— To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)–Leiden mice beyond its cholesterol-lowering effect.

Methods and Results— ApoE*3–Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding was continued or mice received HC supplemented with 0.002% (w/w) atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice received a low-cholesterol (LC) diet to establish a plasma cholesterol level similar to that achieved in the HC+A group. HC+A and LC diet reduced, significantly and to the same extent, lesion progression and complication in the aortic root, as assessed by measuring total atherosclerotic lesion area, lesion severity, and macrophage and smooth muscle cell area. In the aortic arch, HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular inflammation (ie, expression of macrophage migration inhibitory factor , plasminogen activator inhibitor- 1, matrix metalloproteinase-9), but HC+A additionally suppressed vascular cell adhesion molecule-1 expression and, in parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no antiinflammatory action toward hepatic inflammation markers (serum amyloid A, C-reactive protein [CRP]) in apoE*3–Leiden mice and human CRP transgenic mice.

Conclusion— Low-dose atorvastatin cholesterol-dependently reduces lesion progression in the aortic root but shows antiinflammatory vascular activity and tends to retard atherogenesis in the aortic arch beyond its cholesterol-lowering effect.

We evaluated whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation independent of its cholesterol-lowering effect in apoE*3–Leiden mice carrying preexisting mild lesions. Atorvastatin tended to retard atherogenesis in the aortic arch beyond cholesterol lowering and reduced inflammation (ie, VCAM-1 expression and monocyte adhesion) independently of cholesterol lowering.

Key Words: lipids • lipoprotein metabolism • growth factors • pathophysiology

This article has been cited by other articles:

				J. Gronros, J. Wikstrom, U. Brandt-Eliasson, G. B. Forsberg, M. Behrendt, G. I. Hansson, and L. M. Gan Effects of rosuvastatin on cardiovascular morphology and function in an ApoE-knockout mouse model of atherosclerosis Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H2046 - H2053. [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]

				A. S. M. Zadelaar, L. S.M. Boesten, J. W. Jukema, B. J.M. van Vlijmen, T. Kooistra, J. J. Emeis, E. Lundholm, G. Camejo, and L. M. Havekes Dual PPAR{alpha}/{gamma} Agonist Tesaglitazar Reduces Atherosclerosis in Insulin-Resistant and Hypercholesterolemic ApoE*3Leiden Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2560 - 2566. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, F. A. Jaffer, K. A. Kelly, D. E. Sosnovik, E. Aikawa, P. Libby, and R. Weissleder Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis Circulation, October 3, 2006; 114(14): 1504 - 1511. [Abstract] [Full Text] [PDF]

				T. Kooistra, L. Verschuren, J. de Vries-van der Weij, W. Koenig, K. Toet, H.M.G. Princen, and R. Kleemann Fenofibrate Reduces Atherogenesis in ApoE*3Leiden Mice: Evidence for Multiple Antiatherogenic Effects Besides Lowering Plasma Cholesterol Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2322 - 2330. [Abstract] [Full Text] [PDF]

				D. Rein, E. Schijlen, T. Kooistra, K. Herbers, L. Verschuren, R. Hall, U. Sonnewald, A. Bovy, and R. Kleemann Transgenic Flavonoid Tomato Intake Reduces C-Reactive Protein in Human C-Reactive Protein Transgenic Mice More Than Wild-Type Tomato J. Nutr., September 1, 2006; 136(9): 2331 - 2337. [Abstract] [Full Text] [PDF]

				I. Duivenvoorden, P. J Voshol, P. C. Rensen, W. van Duyvenvoorde, J. A Romijn, J. J Emeis, L. M Havekes, and W. F Nieuwenhuizen Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice. Am. J. Clinical Nutrition, August 1, 2006; 84(2): 312 - 321. [Abstract] [Full Text] [PDF]