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 language | English |
|---|---|
| Pages (from-to) | 434-441 |
| Number of pages | 8 |
| Journal | Journal of Cellular Physiology |
| Volume | 214 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2008 |
| Externally published | Yes |
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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 journal › Article
}
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.
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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 -