TY - JOUR
T1 - 6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing BMP signalling
AU - Kurakula, Kondababu
AU - Sun, Xiao-Qing
AU - Happé, Chris
AU - da Silva Goncalves Bos, Denielli
AU - Szulcek, Robert
AU - Schalij, Ingrid
AU - Wiesmeijer, Karien
AU - Lodder, Kirsten
AU - Tu, Ly
AU - Guignabert, Christophe
AU - de Vries, Carlie J
AU - de Man, Frances
AU - Noordegraaf, Anton Vonk
AU - Ten Dijke, Peter
AU - Goumans, Marie-José
AU - Bogaard, Harm Jan
PY - 2019
Y1 - 2019
N2 - 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 the impaired BMP signaling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine would improve the 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 signaling 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-mercaptopurine markedly restored MVEC function by normalising proliferation, inflammation and BMP signaling. Finally, 6-mercaptopurine 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.
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 the impaired BMP signaling and vascular remodelling in PAH is unknown.We hypothesised that activation of Nur77 by 6-mercaptopurine would improve the 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 signaling 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-mercaptopurine markedly restored MVEC function by normalising proliferation, inflammation and BMP signaling. Finally, 6-mercaptopurine 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.
UR - http://www.mendeley.com/research/6mercaptopurine-agonist-nur77-reduces-progression-pulmonary-hypertension-enhancing-bmp-signalling
M3 - Article
SN - 0903-1936
JO - The European Respiratory Journal
JF - The European Respiratory Journal
ER -