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

OBJECTIVE: The peroxisome proliferator activated receptor-gamma (PPARgamma) 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 PPARgamma 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 PPARgamma 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 PPARgamma (PPARgamma(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 PPARgamma(L/+) SMCs. After arterial injury, PPARgamma(L/+) mice had a approximately 4.3-fold increase in the development of intimal hyperplasia. CONCLUSIONS: These findings are consistent with a normal role for PPARgamma in inhibiting SMC migration and proliferation in the context of restenosis or atherosclerosis.