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 Wiesmeijer, Kirsten Lodder, Ly Tu, Christophe Guignabert, Carlie J de Vries, Frances 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
Publication statusPublished - 2019

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