Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse

Objective: Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) alpha/beta agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPAR alpha/gamma agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development. Methods: Six-week-old male apoE KO mice were randomised to receive the dual PPAR alpha/gamma agonist, compound 3q (3 mg/kg/day), the PPAR gamma agonist, rosiglitazone (20 mg/kg/day), the PPAR alpha agonist, gemfibrozil (100 mg/kg/day) by gavage or no treatment for 20 weeks (n = 12/group). Results: Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p < 0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p < 0.001), P-selectin (3.4-fold, p < 0.001) monocyte chemoattractant protein-1 (3.4-fold; p < 0.001) as well as the scavenger receptor, CD36 (2-fold, p < 0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPAR alpha and gamma agonists used individually. Conclusion: The finding of increased atherogenesis following a dual PPAR alpha/gamma agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches. (c) 2006 Elsevier Ireland Ltd. All rights reserved.