Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling

Kondababu Kurakula, Xiao-Qing Sun, Chris Happé, Denielli da Silva Goncalves Bos, Robert Szulcek, Ingrid Schalij, Karien C. Wiesmeijer, Kirsten Lodder, Ly Tu, Christophe Guignabert, Carlie J. M. de Vries, Frances S. de Man, Anton Vonk Noordegraaf, Peter ten Dijke, Marie-José Goumans, Harm Jan Bogaard

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
JournalThe European respiratory journal
Volume54
Issue number3
Early online date4 Jul 2019
DOIs
Publication statusPublished - 2019

Cite this

Kurakula, Kondababu ; Sun, Xiao-Qing ; Happé, Chris ; da Silva Goncalves Bos, Denielli ; Szulcek, Robert ; Schalij, Ingrid ; Wiesmeijer, Karien C. ; Lodder, Kirsten ; Tu, Ly ; Guignabert, Christophe ; de Vries, Carlie J. M. ; de Man, Frances S. ; Vonk Noordegraaf, Anton ; ten Dijke, Peter ; Goumans, Marie-José ; Bogaard, Harm Jan. / Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling. In: The European respiratory journal. 2019 ; Vol. 54, No. 3.
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title = "Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling",
abstract = "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.",
author = "Kondababu Kurakula and Xiao-Qing Sun and Chris Happ{\'e} and {da Silva Goncalves Bos}, Denielli and Robert Szulcek and Ingrid Schalij and Wiesmeijer, {Karien C.} and Kirsten Lodder and Ly Tu and Christophe Guignabert and {de Vries}, {Carlie J. M.} and {de Man}, {Frances S.} and {Vonk Noordegraaf}, Anton and {ten Dijke}, Peter and Marie-Jos{\'e} Goumans and Bogaard, {Harm Jan}",
note = "Copyright {\circledC}ERS 2019.",
year = "2019",
doi = "10.1183/13993003.02400-2018",
language = "English",
volume = "54",
journal = "European Respiratory Journal",
issn = "0903-1936",
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Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: role of BMP signalling. / Kurakula, Kondababu; Sun, Xiao-Qing; Happé, Chris; da Silva Goncalves Bos, Denielli; Szulcek, Robert; Schalij, Ingrid; Wiesmeijer, Karien C.; Lodder, Kirsten; Tu, Ly; Guignabert, Christophe; de Vries, Carlie J. M.; de Man, Frances S.; Vonk Noordegraaf, Anton; ten Dijke, Peter; Goumans, Marie-José; Bogaard, Harm Jan.

In: The European respiratory journal, Vol. 54, No. 3, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Prevention of progression of pulmonary hypertension by the Nur77 agonist 6-mercaptopurine: 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 - Copyright ©ERS 2019.

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 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.

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