The dual PPARalpha/gamma agonist tesaglitazar blocks progression of pre-existing atherosclerosis in APOE*3Leiden.CETP transgenic mice.

BACKGROUND AND PURPOSE: We have evaluated the effects of a peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice. EXPERIMENTAL APPROACH: E3L.CETP mice were fed a high-cholesterol diet for 11 weeks to induce atherosclerosis, followed by a low-cholesterol diet for 4 weeks to obtain a lower plasma total cholesterol level of approximately 10 mmol.L(-1). Mice were divided into three groups, which were either killed before (baseline) or after an 8 week treatment period with low-cholesterol diet without (control) or with the PPARalpha/gamma agonist tesaglitazar (10 microg.kg(-1).day(-1)). Atherosclerosis was assessed in the aortic root. KEY RESULTS: Treatment with tesaglitazar significantly reduced plasma triglycerides, total cholesterol, CETP mass and CETP activity, and increased high-density lipoprotein-cholesterol. At baseline, substantial atherosclerosis had developed. During the 8 week low-cholesterol diet, atherosclerosis progressed in the control group with respect to lesion area and severity, whereas tesaglitazar inhibited lesion progression during this period. Tesaglitazar reduced vessel wall inflammation, as reflected by decreased monocyte adhesion and macrophage area, and modified lesions to a more stabilized phenotype, with increased smooth muscle cell content in the cap and collagen content. CONCLUSIONS AND IMPLICATIONS: Dual PPARalpha/gamma agonism with tesaglitazar markedly improved the atherogenic triad by reducing triglycerides and very low-density lipoprotein-cholesterol and increasing high-density lipoprotein-cholesterol and additionally reduced cholesterol-induced vessel wall activation. These actions resulted in complete inhibition of progression and stabilization of pre-existing atherosclerotic lesions in E3L.CETP mice.