Published online before print July 24, 2003, doi: 10.1161/01.RES.0000088344.15288.E6
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© 2003 American Heart Association, Inc.
UltraRapid Communication |
Regulation of the Growth Arrest and DNA Damage-Inducible Gene 45 (GADD45) by Peroxisome Proliferator-Activated Receptor 
in Vascular Smooth Muscle Cells
From the Division of Endocrinology, Diabetes and Hypertension and The Gonda (Goldschmied) Diabetes Center (D.B., F.Y., J.L., F.B., A.J.V.H., R.E.L.), David Geffen School of Medicine, University of California, Los Angeles, Calif; Department of Medicine/Cardiology (D.B., F.B., E.F.), German Heart Institute, Berlin, Germany; Merck Research Laboratories (J.P.B.), Rahway, NJ; Department of Preventive Medicine (T.S.), Kyoto Prefectural University of Medicine, Kawaramachi-Hiokoji, Kamigyo-ku, Kyoto, Japan; Division of Molecular Medicine and The Gonda Diabetes and Genetic Research Center, and the Department of Diabetes, Endocrinology, and Metabolism (B.M.F.), The City of Hope National Medical Center, Beckman Research Institute, Duarte, Calif.
Correspondence to Ronald E. Law, PhD, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095. E-mail rlaw{at}mednet.ucla.edu
Peroxisome proliferator-activated receptor (PPAR) 
is activated by thiazolidinediones (TZDs), widely used as insulin-sensitizing agents for the treatment of type 2 diabetes. TZDs have been shown to induce apoptosis in a variety of mammalian cells. In vascular smooth muscle cells (VSMCs), proliferation and apoptosis may be competing processes during the formation of restenotic and atherosclerotic lesions. The precise molecular mechanisms by which TZDs induce apoptosis in VSMCs, however, remain unclear. In the present study, we demonstrate that the TZDs rosiglitazone (RSG), troglitazone (TRO), and a novel non-TZD partial PPAR agonist (nTZDpa) induce caspase-mediated apoptosis of human coronary VSMCs. Induction of VSMC apoptosis correlated closely with an upregulation of growth arrest and DNA damage-inducible gene 45 (GADD45) mRNA expression and transcription, a well-recognized modulator of cell cycle arrest and apoptosis. Using adenoviral-mediated overexpression of a constitutively active PPAR mutant and the irreversible PPAR antagonist GW9662, we provide evidence that PPAR ligands induce caspase-mediated apoptosis and GADD45 expression through a receptor-dependent pathway. Deletion analysis of the GADD45 promoter revealed that a 153-bp region between -234 and -81 bp proximal to the transcription start site, containing an Oct-1 element, was crucial for the PPAR ligand–mediated induction of the GADD45 promoter. PPAR activation induced Oct-1 protein expression and DNA binding and stimulated activity of a reporter plasmid driven by multiple Oct-1 elements. These findings suggest that activation of PPAR can lead to apoptosis and growth arrest in VSMCs, at least in part, by inducing Oct-1–mediated transcription of GADD45. The full text of this article is available online at http://www.circresaha.org.
Key Words: peroxisome proliferator-activated receptor • apoptosis • vascular smooth muscle • octamer transcription factor
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