Tesaglitazar lowers CETP mass and activity and halts progression of existing atherosclerosis in CETP-transgenic mice (Br J Pharmacol 2009)

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

Br J Pharmacol · 13 February 2009 · 7

van der Hoorn JW, Jukema JW, Havekes LM, Lundholm E, Camejo G, Rensen PC, Princen HM

In APOE*3Leiden.CETP transgenic mice with pre-existing atherosclerosis induced by 11 weeks of high-cholesterol feeding, an 8-week treatment period with the dual PPARalpha/gamma agonist tesaglitazar significantly reduced plasma triglycerides, total cholesterol, CETP mass, and CETP activity while raising HDL-cholesterol. Untreated control mice showed continued lesion progression in area and severity over this period, whereas tesaglitazar completely halted lesion progression, reduced vessel wall inflammation (less monocyte adhesion and macrophage area), and shifted lesions toward a more stable phenotype with more smooth muscle cells and collagen in the cap. Dual PPARalpha/gamma agonism thus stabilized and stopped progression of pre-existing atherosclerotic lesions in this CETP-expressing model.

Original abstract

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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.