Dominant-Negative Loss of PPARγ Function Enhances Smooth Muscle Cell Proliferation, Migration, and Vascular Remodeling

Objective-The peroxisome proliferator activated receptor-gamma (PPAR gamma) protein is a nuclear transcriptional activator with importance in diabetes management as the molecular target for the thiazolidinedione (TZD) family of drugs. Substantial evidence indicates that the TZD family of PPAR gamma agonists may retard the development of atherosclerosis. However, recent clinical data have suggested that at least one TZD may increase the risk of myocardial infarction and death from cardiovascular disease. In this study, we used a genetic approach to disrupt PPAR gamma signaling to probe the protein's role in smooth muscle cell (SMC) responses that are important for atherosclerosis. Methods and Results-SMC isolated from transgenic mice harboring the dominate-negative P465L mutation in PPAR gamma (PPAR gamma(L/+)) exhibited greater proliferation and migration then did wild-type cells. Upregulation of ETS-1, but not ERK activation, correlated with enhanced proliferative and migratory responses PPAR gamma(L/+) SMCs. After arterial injury, PPAR gamma(L/+) mice had a approximate to 4.3-fold increase in the development of intimal hyperplasia. Conclusion-These findings are consistent with a normal role for PPAR gamma in inhibiting SMC migration and proliferation in the context of restenosis or atherosclerosis. (Arterioscler Thromb Vasc Biol. 2009; 29: 465-471.)