TY - JOUR T1 - 6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing BMP signalling JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.02400-2018 SP - 1802400 AU - Kondababu Kurakula AU - Xiao-Qing Sun AU - Chris Happé AU - Denielli da Silva Goncalves Bos AU - Robert Szulcek AU - Ingrid Schalij AU - Karien C. Wiesmeijer AU - Kirsten Lodder AU - Ly Tu AU - Christophe Guignabert AU - Carlie J. M. de Vries AU - Frances S. de Man AU - Anton Vonk Noordegraaf AU - Peter ten Dijke AU - Marie-José Goumans AU - Harm Jan Bogaard Y1 - 2019/01/01 UR - http://erj.ersjournals.com/content/early/2019/07/24/13993003.02400-2018.abstract 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.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Sun has nothing to disclose.Conflict of interest: Dr. Happé has nothing to disclose.Conflict of interest: Dr. da Silva Goncalves Bos has nothing to disclose.Conflict of interest: Dr. Szulcek has nothing to disclose.Conflict of interest: Dr. Schalij has nothing to disclose.Conflict of interest: Dr. Lodder has nothing to disclose.Conflict of interest: Dr. Tu has nothing to disclose.Conflict of interest: Dr. Guignabert has nothing to disclose.Conflict of interest: Dr. ten Dijke has nothing to disclose.Conflict of interest: Dr. Goumans has nothing to disclose.Conflict of interest: Dr. Bogaard has nothing to disclose.Conflict of interest: Dr. C. Wiesmeijer has nothing to disclose.Conflict of interest: Dr. J.M. de Vries has nothing to disclose.Conflict of interest: Dr. S. de Man has nothing to disclose.Conflict of interest: Dr. Vonk Noordegraaf has nothing to disclose.Conflict of interest: Dr. Kurakula has nothing to disclose. ER -