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) α/γ agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARα/γ 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 PPARα/γ agonist, compound 3q (3 mg/kg/day), the PPARγ agonist, rosiglitazone (20 mg/kg/day), the PPARα 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 PPARα and γ agonists used individually. Conclusion: The finding of increased atherogenesis following a dual PPARα/γ agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches.