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

Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterised by abnormal remodelling of pulmonary vessels, leading to increased vascularresistance and right ventriclefailure. This abnormal vascularremodelling 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 vascularcells, but its role in the impaired BMP signaling and vascularremodelling in PAH is unknown. We hypothesised that activation of Nur77 by 6- mercaptopurinewould improve the PAH by inhibiting endothelial cell dysfunction and vascularremodelling. 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- mercaptopurinemarkedly restored MVEC function by normalising proliferation, inflammation and BMP signaling. Finally, 6- mercaptopurineprevented and reversed abnormal vascularremodelling and right ventriclehypertrophy in the sugen-hypoxia rat model of severe angioproliferative PAH. Our data demonstrate that Nur77 is a critical modulator in PAH by inhibiting vascularremodelling and increasing BMP signalling, and activation of Nur77 could be a promising option for the treatment of PAH.