TY - JOUR
T1 - Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling
T2 - Role of 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 C.
AU - Lodder, Kirsten
AU - Tu, Ly
AU - Guignabert, Christophe
AU - de Vries, Carlie J. M.
AU - de Man, Frances S.
AU - Vonk Noordegraaf, Anton
AU - ten Dijke, Peter
AU - Goumans, Marie-José
AU - Bogaard, Harm Jan
N1 - Funding Information: Support statement: We acknowledge support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences grant 2012–08 awarded to the Phaedra consortium (www.phaedraresearch.nl). We also acknowledge support for K. Kurakula by the Grants4Targets (Bayer AG) grant 2016-03-1554 and by the Dutch Lung Foundation (Longfonds) grant 5.2.17.198J0. Funding information for this article has been deposited with the Crossref Funder Registry. Publisher Copyright: Copyright © ERS 2019
PY - 2019/9/1
Y1 - 2019/9/1
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 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.
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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072746394&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31273046
UR - http://www.scopus.com/inward/record.url?scp=85072746394&partnerID=8YFLogxK
U2 - https://doi.org/10.1183/13993003.02400-2018
DO - https://doi.org/10.1183/13993003.02400-2018
M3 - Article
C2 - 31273046
SN - 0903-1936
VL - 54
JO - European respiratory journal
JF - European respiratory journal
IS - 3
M1 - 1802400
ER -