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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:465.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

Dane Meredith; Manikandan Panchatcharam; Sumitra Miriyala; Yau-Sheng Tsai; Andrew J. Morris; Nobuyo Maeda; George A. Stouffer; Susan S. Smyth

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.

Correspondence to Susan S. Smyth, MD, PhD, The Gill Heart Institute, 326 Charles T Wethington Building, 900 S. Limestone Street, Lexington, KY 40536. 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 (PPAR^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^L/+ SMCs. After arterial injury, PPAR^L/+ 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.

We applied a genetic approach to investigate the normal role of PPAR in the regulation of smooth muscle cell (SMC) function. Dominate-negative disruption of PPAR function by the P465L mutation increased proliferation, migration, and ETS-1 but not ERK activation, and promoted the development intimal hyperplasia after arterial injury.

Key Words: PPAR • smooth muscle cell • restenosis