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


Autoria(s): Ward, Jane E.; Gould, Haslinda; Harris, Trudi; Bonacci, John V.; Stewart, Alastair G.
Data(s)

01/02/2004

Resumo

<b>1.</b> 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.<br /><br /><b>2.</b> 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).<br /><br /><b>3.</b> 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.<br /><br /><b>4.</b> 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.<br /><br /><b>5.</b> 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.<br /><br /><b>6.</b> 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.<br />

Identificador

http://hdl.handle.net/10536/DRO/DU:30047632

Idioma(s)

eng

Publicador

John Wiley & Sons

Relação

http://dro.deakin.edu.au/eserv/DU:30047632/gould-pparligands-2004.pdf

http://dx.doi.org/10.1038/sj.bjp.0705630

Direitos

2004, Nature Publishing Group

Palavras-Chave #airway smooth muscle #ciglitazone #15-deoxy-Δ12,14-prostaglandin J2 #GW9662 #peroxisome proliferator-activated receptor γ #PPARγ antagonist #proliferation #rosiglitazone #thiazolidinedione
Tipo

Journal Article