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

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)434-441
Number of pages8
JournalJournal of Cellular Physiology
Volume214
Issue number2
DOIs
Publication statusPublished - Feb 2008
Externally publishedYes

Fingerprint

beraprost
PPAR delta
Epoprostenol
Vascular Smooth Muscle
Smooth Muscle Myocytes
Muscle
Nitric Oxide Synthase
Cells
Peroxisome Proliferator-Activated Receptors
Rats
Balloon Angioplasty
Terminal Repeat Sequences
Balloons

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Molecular mechanisms of the antiproliferative effect of beraprost, a prostacyclin agonist, in murine vascular smooth muscle cells. / Lin, Heng; Lee, Ja Ling; Hou, Hsin Han; Chung, Chih Peng; Hsu, Sung Po; Juan, Shu Hui.

In: Journal of Cellular Physiology, Vol. 214, No. 2, 02.2008, p. 434-441.

Research output: Contribution to journalArticle

@article{420dc758e8c9452d8ef2fc1104c1497e,
title = "Molecular mechanisms of the antiproliferative effect of beraprost, a prostacyclin agonist, in murine vascular smooth muscle cells",
abstract = "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.",
author = "Heng Lin and Lee, {Ja Ling} and Hou, {Hsin Han} and Chung, {Chih Peng} and Hsu, {Sung Po} and Juan, {Shu Hui}",
year = "2008",
month = "2",
doi = "10.1002/jcp.21214",
language = "English",
volume = "214",
pages = "434--441",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Molecular mechanisms of the antiproliferative effect of beraprost, a prostacyclin agonist, in murine vascular smooth muscle cells

AU - Lin, Heng

AU - Lee, Ja Ling

AU - Hou, Hsin Han

AU - Chung, Chih Peng

AU - Hsu, Sung Po

AU - Juan, Shu Hui

PY - 2008/2

Y1 - 2008/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=37349112477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37349112477&partnerID=8YFLogxK

U2 - 10.1002/jcp.21214

DO - 10.1002/jcp.21214

M3 - Article

C2 - 17620284

AN - SCOPUS:37349112477

VL - 214

SP - 434

EP - 441

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 2

ER -