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PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms

Ward, Jane E., Gould, Haslinda, Harris, Trudi, Bonacci, John V. and Stewart, Alastair G. 2004, PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms, British journal of pharmacology, vol. 141, no. 3, pp. 517-525, doi: 10.1038/sj.bjp.0705630.

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Title PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms
Formatted title  PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms
Author(s) Ward, Jane E.
Gould, Haslinda
Harris, Trudi
Bonacci, John V.
Stewart, Alastair G.
Journal name British journal of pharmacology
Volume number 141
Issue number 3
Start page 517
End page 525
Total pages 10
Publisher John Wiley & Sons
Place of publication West Sussex, England
Publication date 2004-02
ISSN 0007-1188
1476-5381
Keyword(s) airway smooth muscle
ciglitazone
15-deoxy-Δ12,14-prostaglandin J2
GW9662
peroxisome proliferator-activated receptor γ
PPARγ antagonist
proliferation
rosiglitazone
thiazolidinedione
Summary 1. The influence of two peroxisome proliferator-activated receptor γ (PPARγ) ligands, a thiazolidinedione, rosiglitazone (RG) and the prostaglandin D2 metabolite 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) on the proliferation of human cultured airway smooth muscle (HASM) was examined.

2. The increases in HASM cell number in response to basic fibroblast growth factor (bFGF, 300 pm) or thrombin (0.3 U ml−1) were significantly inhibited by either RG (1–10 μm) or 15d-PGJ2 (1–10 μm). The effects of RG, but not 15d-PGJ2, were reversed by the selective PPARγ antagonist GW9662 (1 μm).

3. Neither RG nor 15d-PGJ2 (10 μm) decreased cell viability, or induced apoptosis, suggesting that the regulation of cell number was due to inhibition of proliferation, rather than increased cell death.

4. Flow-cytometric analysis of HASM cell cycle distribution 24 h after bFGF addition showed that RG prevented the progression of cells from G1 to S phase. In contrast, 15d-PGJ2 caused an increase in the proportion of cells in S phase, and a decrease in G2/M, compared to bFGF alone.

5. Neither RG nor 15d-PGJ2 inhibited ERK phosphorylation measured 6 h post mitogen addition. The bFGF-mediated increase in cyclin D1 protein levels after 8 h was reduced in the presence of 15d-PGJ2, but not RG.

6. Although both RG and 15d-PGJ2 can inhibit proliferation of HASM irrespective of the mitogen used, only the antiproliferative effects of RG appear to be PPARγ-dependent. The different antimitogenic mechanisms of 15d-PGJ2 and synthetic ligands for PPARγ may be exploited to optimise the potential for these compounds to inhibit airway remodelling in asthma.
Language eng
DOI 10.1038/sj.bjp.0705630
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2004, Nature Publishing Group
Persistent URL http://hdl.handle.net/10536/DRO/DU:30047632

Document type: Journal Article
Collection: School of Medicine
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