6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing 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 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.

Original languageEnglish
JournalThe European respiratory journal
DOIs
Publication statusE-pub ahead of print - 4 Jul 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 ; Noordegraaf, Anton Vonk ; Ten Dijke, Peter ; Goumans, Marie-José ; Bogaard, Harm Jan. / 6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing BMP signalling. In: The European respiratory journal. 2019.
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title = "6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing 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 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.",
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 Noordegraaf, {Anton Vonk} and {Ten Dijke}, Peter and Marie-Jos{\'e} Goumans and Bogaard, {Harm Jan}",
note = "Copyright {\circledC}ERS 2019.",
year = "2019",
month = "7",
day = "4",
doi = "10.1183/13993003.02400-2018",
language = "English",
journal = "European Respiratory Journal",
issn = "0903-1936",
publisher = "European Respiratory Society",

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Kurakula, K, Sun, X-Q, Happé, C, da Silva Goncalves Bos, D, Szulcek, R, Schalij, I, Wiesmeijer, KC, Lodder, K, Tu, L, Guignabert, C, de Vries, CJM, de Man, FS, Noordegraaf, AV, Ten Dijke, P, Goumans, M-J & Bogaard, HJ 2019, '6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing BMP signalling' The European respiratory journal. https://doi.org/10.1183/13993003.02400-2018

6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing 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; Noordegraaf, Anton Vonk; Ten Dijke, Peter; Goumans, Marie-José; Bogaard, Harm Jan.

In: The European respiratory journal, 04.07.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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 C

AU - Lodder, Kirsten

AU - Tu, Ly

AU - Guignabert, Christophe

AU - de Vries, Carlie J M

AU - de Man, Frances S

AU - Noordegraaf, Anton Vonk

AU - Ten Dijke, Peter

AU - Goumans, Marie-José

AU - Bogaard, Harm Jan

N1 - Copyright ©ERS 2019.

PY - 2019/7/4

Y1 - 2019/7/4

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.

U2 - 10.1183/13993003.02400-2018

DO - 10.1183/13993003.02400-2018

M3 - Article

JO - European Respiratory Journal

JF - European Respiratory Journal

SN - 0903-1936

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