Abstract
肺动脉高血压(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.
Abstract
Pharmacological activation of Nur77 with 6-mercaptopurine reduces the progression of pulmonary hypertension by enhancing BMP signallinghttp://bit.ly/2KINWCW
Footnotes
This article has supplementary material available fromwww.qdcxjkg.com
Support statement: We acknowledge support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences grant 2012–08 awarded to the Phaedra consortium (www.phaedraresearch.nl). We also acknowledge support for K. Kurakula by the Grants4Targets (Bayer AG) grant 2016-03-1554 and by the Dutch Lung Foundation (Longfonds) grant 5.2.17.198J0. Funding information for this article has been deposited with theCrossref Funder Registry.
Conflict of interest: X-Q. Sun has nothing to disclose.
Conflict of interest: C. Happé has nothing to disclose.
Conflict of interest: D. da Silva Goncalves Bos has nothing to disclose.
Conflict of interest: R. Szulcek has nothing to disclose.
Conflict of interest: I. Schalij has nothing to disclose.
Conflict of interest: K.C. Wiesmeijer has nothing to disclose.
Conflict of interest: K. Lodder has nothing to disclose.
Conflict of interest: L. Tu has nothing to disclose.
Conflict of interest: C. Guignabert has nothing to disclose.
Conflict of interest: C.J.M. de Vries has nothing to disclose.
Conflict of interest: F.S. de Man has nothing to disclose.
Conflict of interest: A. Vonk Noordegraaf has nothing to disclose.
Conflict of interest: P. ten Dijke has nothing to disclose.
Conflict of interest: M-J. Goumans has nothing to disclose.
Conflict of interest: H.J. Bogaard has nothing to disclose.
Conflict of interest: K. Kurakula has nothing to disclose.
- ReceivedDecember 18, 2018.
- AcceptedJune 19, 2019.
- Copyright ©ERS 2019