Pharmacological activation of Nur77 enhances BMP signalling and inhibits vascular remodelling in pulmonary arterial hypertension
K. Kurakula (Leiden, Netherlands), X. Sun (Amsterdam, Netherlands), C. Happé (Amsterdam, Netherlands), M. Goumans (Leiden, Netherlands), H. Bogaard (Amsterdam, Netherlands)
Source: International Congress 2018 – Pathobiology of pulmonary hypertension
Session: Pathobiology of pulmonary hypertension
Session type: Poster Discussion
Number: 3937
Disease area: Pulmonary vascular diseases
Abstract Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance, right ventricle failure and death. This abnormal vascular remodelling is associated with endothelial cell (EC) dysfunction, increased proliferation of smooth muscle cells (SMCs), inflammation, and impaired bone morphogenetic protein (BMP) signalling. However, the cause of the impaired BMP signaling and vascular remodeling remains unknown. Orphan nuclear receptor Nur77 is a key regulator of proliferation and inflammation in vascular cells. Here, we describe that Nur77 is protective against EC dysfunction and vascular remodelling in PAH. Nur77 expression is decreased in human pulmonary microvascular ECs (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 SMCs. Pharmacological activation of Nur77 by 6-mercaptopurine markedly restored MVEC function by normalizing proliferation, inflammation and BMP signalling in vitro. Finally, 6-mercaptopurine prevented and reversed abnormal vascular remodelling and right ventricle hypertrophy in vivo. Thus, 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.
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K. Kurakula (Leiden, Netherlands), X. Sun (Amsterdam, Netherlands), C. Happé (Amsterdam, Netherlands), M. Goumans (Leiden, Netherlands), H. Bogaard (Amsterdam, Netherlands). Pharmacological activation of Nur77 enhances BMP signalling and inhibits vascular remodelling in pulmonary arterial hypertension. 3937
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