PPAR γ ligands, 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms
2004; Wiley; Volume: 141; Issue: 3 Linguagem: Inglês
10.1038/sj.bjp.0705630
ISSN1476-5381
AutoresJane Ward, Haslinda Gould, Trudi Harris, John V Bonacci, Alastair G. Stewart,
Tópico(s)NF-κB Signaling Pathways
ResumoThe influence of two peroxisome proliferator‐activated receptor γ (PPAR γ ) ligands, a thiazolidinedione, rosiglitazone (RG) and the prostaglandin D 2 metabolite 15‐deoxy‐Δ 12,14 ‐prostaglandin J 2 (15d‐PGJ 2 ) on the proliferation of human cultured airway smooth muscle (HASM) was examined. The increases in HASM cell number in response to basic fibroblast growth factor (bFGF, 300 p M ) or thrombin (0.3 U ml −1 ) were significantly inhibited by either RG (1–10 μ M ) or 15d‐PGJ 2 (1–10 μ M ). The effects of RG, but not 15d‐PGJ 2 , were reversed by the selective PPAR γ antagonist GW9662 (1 μ M ). Neither RG nor 15d‐PGJ 2 (10 μ M ) decreased cell viability, or induced apoptosis, suggesting that the regulation of cell number was due to inhibition of proliferation, rather than increased cell death. 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‐PGJ 2 caused an increase in the proportion of cells in S phase, and a decrease in G2/M, compared to bFGF alone. Neither RG nor 15d‐PGJ 2 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‐PGJ 2 , but not RG. Although both RG and 15d‐PGJ 2 can inhibit proliferation of HASM irrespective of the mitogen used, only the antiproliferative effects of RG appear to be PPAR γ ‐dependent. The different antimitogenic mechanisms of 15d‐PGJ 2 and synthetic ligands for PPAR γ may be exploited to optimise the potential for these compounds to inhibit airway remodelling in asthma. British Journal of Pharmacology (2004) 141 , 517–525. doi: 10.1038/sj.bjp.0705630
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