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S111 BONE MORPHOGENETIC PROTEIN 9 INCREASES ENDOTHELIN-1 RELEASE BY HUMAN PULMONARY ARTERY ENDOTHELIAL CELLS VIA A MAPK-DEPENDENT PATHWAY
1J. E. S. Park, 2P. D. Upton, 1P. M. de Souza, 2R. J. Davies, 2N. W. Morrell, 1M. J. D. Griffiths, 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
Introduction Mutations in the bone morphogenetic protein (BMP) receptor II (BMPR-II), a member of the transforming growth factor β (TGFβ) receptor superfamily, are associated with familial pulmonary artery hypertension (PAH), whilst mutations of activin receptor-like kinase-1 (Alk-1) cause hereditary haemorrhagic telangiectasia (HHT). BMP9 binds BMPRII/Alk-1 complex in endothelial cells (ECs) and is reported to be a vascular quiescence factor.1 In addition, constitutively active Alk-1 in ECs induces endothelin-1 (ET-1) production, a contributor to vascular remodelling. Dysregulation of these pathways may therefore affect vascular integrity, as seen in both disease processes. We aimed to investigate the effect of BMP9 on ET-1 regulation.
Methods Human pulmonary artery endothelial cells (HPAECs) were treated with BMP9 (0–100 ng/ml) for up to 24 h in the presence/absence of mitogen-activated protein kinase (MAPK) pathway inhibitors (UO126, SB203580, SP600125; all 3 μM) and an inhibitor of IκB kinase 2 (IKK-2) phosphorylation (SC514, 3 μM), a component of the canonical nuclear factor-κB (NF-κB) pathway. MAPK phosphorylation was assessed by western analysis of whole-cell lysates. ET-1 gene expression and levels in supernatant were quantified.
Results BMP9 stimulated dose-dependent ET-1 release by HPAECs and increased ET-1 gene expression. A significant increase in ET-1 release was seen at physiological levels of BMP9 (1 ng/ml: p<0.001). ET-1 release was attenuated by inhibition of MAPK kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 phosphorylation (p<0.05 and p<0.01 respectively; see fig 1), but not c-Jun N-terminal kinase (JNK) and IKK-2 phosphorylation.
Conclusion BMP9 at physiological doses stimulates …
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