Premium
Molecular mechanisms of the antiproliferative effect of beraprost, a prostacyclin agonist, in murine vascular smooth muscle cells
Author(s) -
Lin Heng,
Lee JaLing,
Hou HsinHan,
Chung ChihPeng,
Hsu SungPo,
Juan ShuHui
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21214
Subject(s) - prostacyclin , agonist , vascular smooth muscle , microbiology and biotechnology , chemistry , pharmacology , smooth muscle , medicine , endocrinology , biology , receptor , biochemistry
Prostacyclin (PGI 2 ) has been shown to inhibit proliferation in vascular smooth muscle cells. To clarify the underlying molecular mechanism, we investigated the vasoprotection of beraprost (a PGI 2 agonist) both in vivo and in vitro. Beraprost eliminated increases in proliferation of rat aortic smooth muscle cells (RASMCs) by 12‐O‐tetradecanoylphorbol 13‐acetate, and enhanced the peroxisome proliferator‐activated receptor‐delta (PPARδ) and inducible nitric oxide synthetase (iNOS) expressions, which were associated with the antiproliferative action of beraprost according to inhibition experiments by [ 3 H]thymidine incorporation. Additionally, elimination of iNOS activity by PPARδ antagonists suggested that iNOS is the downstream target of PPARδ. Furthermore, beraprost increased both consensus PPARδ‐responsive element (PPRE)‐driven luciferase activity and the binding activity of the PPARδ to the putative PPRE in the iNOS promoter; nevertheless, it was abolished by PPARδ antagonists. Deletion of PPRE (−1,349/−1,330) in the iNOS promoter region (−1,359/+2) strongly reduced promoter‐driven activity, representing a novel mechanism of iNOS induction by beraprost. Consistent with this, PPARδ and the concomitant iNOS induction by beraprost were also evident in vivo. Beraprost‐mediated protection in a murine model of balloon angioplasty was significantly attenuated by 13S‐HODE, a PPARδ antagonist. Taken together, the results suggest that the causal relationship between PPARδ and iNOS contributes to the vasoprotective action of beraprost in RASMCs. J. Cell. Physiol. 214: 434–441, 2008. © 2007 Wiley‐Liss, Inc.