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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2560.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Dual PPAR/ Agonist Tesaglitazar Reduces Atherosclerosis in Insulin-Resistant and Hypercholesterolemic ApoE*3Leiden Mice

A. Susanne M. Zadelaar; Lianne S.M. Boesten; J. Wouter Jukema; Bart J.M. van Vlijmen; Teake Kooistra; Jef J. Emeis; Erik Lundholm; German Camejo; Louis M. Havekes

From the Department of Cardiology (A.S.M.Z., J.W.J., L.M.H.), Leiden University Medical Center; TNO-Gaubius Laboratory (A.S.M.Z., L.S.M.B., T.K., J.J.E., L.M.H.), Biomedical Research Unit; Department of General Internal Medicine (L.S.M.B., L.M.H.), Leiden University Medical Center; Hemostasis and Thrombosis Research Center (B.J.M.vV.), Leiden University Medical Center, Leiden, The Netherlands; AstraZeneca (E.L., G.C.), Mölndal, Sweden.

Correspondence to Louis M. Havekes, TNO-Gaubius Laboratory, Biomedical Research Unit, Zernikedreef 9, 2333 CK, P. O. Box 2215, 2301 CE Leiden, The Netherlands. E-mail LM.Havekes{at}pg.tno.nl

Objective— We investigated whether the dual PPAR/ agonist tesaglitazar has anti-atherogenic effects in ApoE*3Leiden mice with reduced insulin sensitivity.

Methods and Results— ApoE*3Leiden transgenic mice were fed a high-fat (HF) insulin-resistance–inducing diet. One group received a high-cholesterol (HC) supplement (1% wt/wt; HC group). A second group received the same HC supplement along with tesaglitazar (T) 0.5 µmol/kg diet (T group). A third (control) group received a low-cholesterol (LC) supplement (0.1% wt/wt; LC group). Tesaglitazar decreased plasma cholesterol by 20% compared with the HC group; cholesterol levels were similar in the T and LC groups. Compared with the HC group, tesaglitazar caused a 92% reduction in atherosclerosis, whereas a 56% reduction was seen in the cholesterol-matched LC group. Furthermore, tesaglitazar treatment significantly reduced lesion number beyond that expected from cholesterol lowering and induced a shift to less severe lesions. Concomitantly, tesaglitazar reduced macrophage-rich and collagen areas. In addition, tesaglitazar reduced inflammatory markers, including plasma SAA levels, the number of adhering monocytes, and nuclear factor B-activity in the vessel wall.

Conclusions— Tesaglitazar has anti-atherosclerotic effects in the mouse model that go beyond plasma cholesterol lowering, possibly caused by a combination of altered lipoprotein profiles and anti-inflammatory vascular effects.

We investigated whether the dual PPAR/ agonist tesaglitazar has anti-atherogenic effects in ApoE*3Leiden transgenic mice with reduced insulin sensitivity. Tesaglitazar has anti-atherosclerotic effects that go beyond plasma cholesterol-lowering. This may be caused by a combination of altered lipoprotein profiles and anti-inflammatory vascular effects.

Key Words: atherosclerosis • cholesterol • inflammation • inhibitors

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