Roles of PPARgamma in preventing the development of atherosclerosis in LDL receptor null mice

Thiazolidinediones are synthetic ligands for peroxisome proliferator activated receptor gamma. They have been demonstrated to possess cardioprotective effects in humans and antiatherogenic properties in animal models. We observed that atherosclerosis in low-density lipoprotein receptor null mice progressed when mice were fed a high-fat diet. Pioglitazone treatment of atherogenic mice prevented this progression of atherosclerosis from its middle stages of disease. However, pioglitazone, in combination with the withdrawal of a high-fat diet, was unable to reverse established atherosclerosis. These findings describe, in part, a general paradox of how therapeutic agents are evaluated in common murine models of atherosclerosis and the lack of therapeutic benefit of agents given to mice with established atherosclerotic lesions, and further, may have implications for human therapy.