PPARdelta-mediated p21/p27 induction via increased CREB-binding protein nuclear translocation in beraprost-induced antiproliferation of murine aortic smooth muscle cells.
We previously showed that an increase in the peroxisome proliferator-activated receptor-delta (PPARdelta), 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 PPARdelta activation. Surprisingly, other than altering the CRE-binding protein (CREB), BPS-mediated PPARdelta 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 PPARdelta 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 PPARdelta activation enhances transcriptional activation of p21/p27 by increasing CBP nuclear translocation, which contributes to the vasoprotective action of BPS.
Sue
Yuh-Mou
YM
Department of Nephrology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Chung
Chih-Peng
CP
Lin
Heng
H
Chou
Ying
Y
Jen
Chih-Yu
CY
Li
Hsiao-Fen
HF
Chang
Chih-Cheng
CC
Juan
Shu-Hui
SH
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047494:PPAR delta; D034741:RNA, Small Interfering; D014665:Vasodilator Agents; D050760:Cyclin-Dependent Kinase Inhibitor p27; C048081:beraprost; D011464:Epoprostenol; D050882:CREB-Binding Protein