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S6 REGULATION OF ENDOTHELIN-1 PRODUCTION BY THE TRANSFORMING GROWTH FACTOR/BONE MORPHOGENETIC PROTEIN PATHWAY IN HUMAN PULMONARY ARTERY SMOOTH MUSCLE CELLS
1P. M. de Souza, 2N. W. Morrell, 2P. D. Upton, 1J. E. S. Park, 1S. J. Wort. 1Unit of Critical Care, NHLI, Imperial College, London, UK, 2University of Cambridge School of Clinical Medicine, Addenbrooke’s/CUHNHSFT and Papworth Hospitals, Cambridge, UK
Background Pulmonary artery hypertension is a fatal condition associated with remodelling of pulmonary resistance vessels. There is convincing evidence for the involvement of both the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) and endothelin (ET-1) pathways in this remodelling process. However, it is unknown how these two pathways interact.
Aim To investigate the effect of TGFβ1, BMP2 and BMP4 on ET-1 release from normal human pulmonary artery smooth muscle cells (HPASMCs).
Methods HPASMCs were grown from resected and morphologically normal pulmonary arteries taken from patients with lung cancer at the Royal Brompton Hospital. Cells were treated with TGFβ1 and/or BMP2 and BMP4 (0, 1 and 10 ng/ml). Following 24 h incubation supernatants were collected and ET-1 concentrations determined by ELISA (R&D, Abingdon, UK). Data were analysed using Student t test.
Results TGFβ1 dose dependently increased ET-1 release from HPASMCs. TGFβ1 (1 ng/ml) significantly increased ET-1 generation by 553% compared with cells treated with medium alone (fig 1; n = 6)). BMP2 (10 ng/ml) and BMP4 (1 and 10 ng/ml) also significantly promoted ET-1 release by up to 20% compared with controls (fig 1; n = 6). When HPASMCs were co-treated with TGFβ1 and BMP2 or BMP4 there was a trend for BMP2 (10 ng/ml) and BMP4 (1 and 10 ng/ml) to attenuate TGFβ1-induced ET-1 release, with only BMP2 at 1 ng/ml significantly inhibiting this release by 24% (fig 1; n = 3).
Conclusion These findings suggest that there may be significant cross-talk between TGFβ/BMP and ET-1 in HPASMCs. Further work is needed to investigate the effect of bone morphogenetic …