Dual PPARα/γ agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemic ApoE*3Leiden mice

OBJECTIVE - We investigated whether the dual PPARα/γ 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 κB-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. © 2006 American Heart Association, Inc. Chemicals / CAS: cholesterol, 57-88-5; collagen, 9007-34-5; tesaglitazar, 251565-85-2; lipid, 66455-18-3; peroxisome proliferator activated receptor alpha, 147258-70-6; 2-ethoxy-3-(4-((4-(methylsulfonyloxy)phenethyl)oxy)phenyl)propanoic acid; Alkanesulfonates; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Biological Markers; Cholesterol, 57-88-5; Cholesterol, Dietary; Collagen, 9007-34-5; Dietary Fats; Lipids; Lipoproteins; NF-kappa B; Phenylpropionates; PPAR alpha; PPAR gamm