Molecular mechanisms of the antiproliferative effect of beraprost, a prostacyclin agonist, in murine vascular smooth muscle cells

Heng Lin, Ja Ling Lee, Hsin Han Hou, Chih Peng Chung, Sung Po Hsu, Shu Hui Juan

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35 引文 斯高帕斯(Scopus)

摘要

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 [ 3H]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.

原文英語
頁(從 - 到)434-441
頁數8
期刊Journal of Cellular Physiology
214
發行號2
DOIs
出版狀態已發佈 - 二月 2008
對外發佈Yes

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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