Raising Levels of Nur77 May Help Halt Progression of PH, Study Suggests
Increasing levels of the receptor Nur77 in cells lining the blood vessels of patients with pulmonary hypertension (PH) may help halt progression of the disease by enhancing the signaling of the BMPR2 gene, often mutated in PH, a study suggests.
The study, “6-mercaptopurine, an agonist of Nur77, reduces progression of pulmonary hypertension by enhancing BMP signaling” was published in the European Respiratory Journal.
Mutations in the BMPR2 gene, which provides instructions for production of a protein called bone morphogenetic protein receptor type 2, were previously identified as a key genetic event found in 80% of patients with hereditary pulmonary arterial hypertension (PAH), and in 30% of those with non-hereditary PAH (called idiopathic PAH). These mutations cause impairments in the BMP signaling pathway, leading to the vascular remodeling that characterizes the disease.
However, the molecular mechanisms underpinning BMP deregulation remain poorly understood.
In the study, researchers at the Netherlands’ Leiden University Medical Center investigated the role of Nur77 in PAH.
“Nur77 is a key regulator of proliferation and inflammation in vascular cells, but its role in the impaired BMP signaling and vascular remodeling in PAH is unknown,” the researchers said.
Nur77 was previously shown to attenuate the release of pro-inflammatory signaling molecules (cytokines), and increasing levels of Nur77 ameliorated experimental PH in mice.
The team therefore hypothesized that the activation of Nur77 “would improve PAH by inhibiting endothelial cell dysfunction and vascular remodeling.”
First, the researchers confirmed that the levels of Nur77 were decreased in microvascular endothelial cells (mvECs) — those lining the blood vessels — from lungs of patients with hereditary and idiopathic PAH, compared to healthy controls. Moreover, low levels of Nur77 were linked with increased expression of pro-inflammatory cytokines.
Increasing the activity of the Nur77 gene modestly but significantly enhanced the levels of BMPR2 and other BMP-linked proteins. Also, researchers saw that increasing Nur77 activity lowered the proliferation and inflammation of mvECs in both control and PAH samples.
Researchers then tested two agonists — chemical substances that stimulate a signaling pathway — of Nur77 called cytosporone B (CsnB) and 6-mercaptopurine (6-MP). Both increased the activity of Nur77 in PAH mvECs. Most importantly, the treatment with both agonists decreased mvECs proliferation.
They then tested the effects of one of the agonists, 6-MP, in mice that had been induced to develop PAH. Treatment with 6-MP at a dose of 7.5 mg/kg/day significantly decreased the right ventricular systolic pressure (RVSP) — a measure of the pressure inside the artery that supplies blood to the lungs (pulmonary artery) — improved the heart’s right ventricle (RV, lower chamber) function, and reduced RV hypertrophy (overgrowth). The treatment also suppressed the remodeling of the lung vasculature.
The team noted that the beneficial effect of 6-MP was associated with rescuing Nur77 activity and BMP signaling.
Overall, the results showed that decreased “Nur77 in the pulmonary vasculature is involved in the pathogenesis of PAH, and that activation of Nur77 by 6-MP could be a novel therapeutic option to reverse the abnormal vascular remodeling and RV hypertrophy in PAH,” the team concluded.