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

Objective - We investigated whether the dual PPAR alpha/gamma 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 mu mol/ 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 kappa 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.