on January 29, 2009
Published online before print January 29, 2009, doi: 10.1161/ATVBAHA.109.184234
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Submitted on January 12, 2009
Accepted on January 20, 2009
Dominant-Negative Loss of PPAR
Function Enhances Smooth Muscle Cell Proliferation, Migration, and Vascular Remodeling
Dane Meredith ;
From the Carolina Cardiovascular Biology Center (D.M., G.A.S.) and the Department of Pathology (Y.-S.T., N.M.), The University of North Carolina at Chapel Hill; the Division of Cardiovascular Medicine (M.P., S.M., A.J.M., S.S.S.), The Gill Heart Institute, University of Kentucky, Lexington; and the Department of Veterans Affairs Medical Center (S.S.S.), Lexington, Kentucky.
* To whom correspondence should be addressed. E-mail: susansmyth{at}uky.edu.
Objective—The peroxisome proliferator activated receptor-gamma (PPAR
) 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 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 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 (PPARL/+) 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 PPARL/+ SMCs. After arterial injury, PPARL/+ mice had a 
4.3-fold increase in the development of intimal hyperplasia.
Conclusion—These findings are consistent with a normal role for PPAR in inhibiting SMC migration and proliferation in the context of restenosis or atherosclerosis.