RT Journal Article
SR Electronic
T1 Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1802400
DO 10.1183/13993003.02400-2018
VO 54
IS 3
A1 Kondababu Kurakula
A1 Xiao-Qing Sun
A1 Chris Happé
A1 Denielli da Silva Goncalves Bos
A1 Robert Szulcek
A1 Ingrid Schalij
A1 Karien C. Wiesmeijer
A1 Kirsten Lodder
A1 Ly Tu
A1 Christophe Guignabert
A1 Carlie J.M. de Vries
A1 Frances S. de Man
A1 Anton Vonk Noordegraaf
A1 Peter ten Dijke
A1 Marie-José Goumans
A1 Harm Jan Bogaard
YR 2019
UL http://erj.ersjournals.com/content/54/3/1802400.abstract
AB Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation and impaired bone morphogenetic protein (BMP) signalling. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in impaired BMP signalling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine (6-MP) would improve PAH by inhibiting endothelial cell dysfunction and vascular remodelling.Nur77 expression is decreased in cultured pulmonary microvascular endothelial cells (MVECs) and lungs of PAH patients. Nur77 significantly increased BMP signalling and strongly decreased proliferation and inflammation in MVECs. In addition, conditioned medium from PAH MVECs overexpressing Nur77 inhibited the growth of healthy smooth muscle cells. Pharmacological activation of Nur77 by 6-MP markedly restored MVEC function by normalising proliferation, inflammation and BMP signalling. Finally, 6-MP prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in the Sugen/hypoxia rat model of severe angioproliferative PAH.Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascular remodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH.Pharmacological activation of Nur77 with 6-mercaptopurine reduces the progression of pulmonary hypertension by enhancing BMP signalling http://bit.ly/2KINWCW