Am J Physiol Cell Physiol AJP: Endocrinology and Metabolism
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Am J Physiol Cell Physiol 297: C321-C329, 2009. First published July 8, 2009; doi:10.1152/ajpcell.00069.2009
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VASCULAR BIOLOGY

PPAR{delta}-mediated p21/p27 induction via increased CREB-binding protein nuclear translocation in beraprost-induced antiproliferation of murine aortic smooth muscle cells

Yuh-Mou Sue,1 Chih-Peng Chung,2 Heng Lin,3 Ying Chou,2 Chih-Yu Jen,2 Hsiao-Fen Li,4 Chih-Cheng Chang,2 and Shu-Hui Juan2,5

1Department of Nephrology, Taipei Medical University-Wan Fang Hospital, Taipei; 2Graduate Institute of Medical Sciences, Taipei Medical University, Taipei; 3Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien; 4Graduate Institute of Life Sciences, National Defense Medical Center; and 5Department of Physiology, Taipei Medical University, Taipei, Taiwan

Submitted 11 February 2009 ; accepted in final form 24 May 2009

We previously showed that an increase in the peroxisome proliferator-activated receptor-{delta} (PPAR{delta}), together with subsequent induction of inducible nitric oxide synthase (iNOS) by beraprost (BPS), inhibits aortic smooth muscle cell proliferation. Herein, we delineated the mechanisms of the antiproliferative effects of BPS through the induction of p21/p27. BPS concentration dependently induced the p21/p27 promoter- and consensus cAMP-responsive element (CRE)-driven luciferase activities, which were significantly suppressed by blocking PPAR{delta} activation. Surprisingly, other than altering the CRE-binding protein (CREB), BPS-mediated PPAR{delta} activation increased nuclear localization of the CREB-binding protein (CBP), a coactivator, which was further confirmed by chromatin immunoprecipitation. Furthermore, novel functional PPAR-responsive elements (PPREs) next to CREs in the rat p21/p27 promoter regions were identified, where PPAR{delta} interacted with CREB through CBP recruitment. BPS-mediated suppression of restenosis in mice with angioplasty was associated with p21/p27 induction. Herein, we demonstrate for the first time that BPS-mediated PPAR{delta} activation enhances transcriptional activation of p21/p27 by increasing CBP nuclear translocation, which contributes to the vasoprotective action of BPS.

cAMP-responsive element; cAMP-responsive element-binding protein; cAMP-responsive element-binding protein-binding protein; antiproliferation


Address for reprint requests and other correspondence: S.-H. Juan, Graduate Institute of Medical Sciences and Dept. of Physiology, Taipei Medical Univ., 250 Wu-Hsing St., Taipei 110, Taiwan (E-mail: juansh{at}tmu.edu.tw)






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