Abstract 20817: Pharmacological Activation of Nuclear Receptor Nur77 Attenuates Experimental Pulmonary Arterial Hypertension by Modulating BMP Signaling

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Abstract

Rationale: Pulmonary arterial hypertension (PAH) is a severe disease characterized by excessive proliferation of endothelial (EC) and smooth muscle cells (SMCs), and impaired BMP signalling in small lung arteries, resulting in increased vascular resistance and subsequent right ventricle failure. Furthermore, inflammation plays a crucial role in the initiation and maintenance of pulmonary vascular remodeling in PAH. Nuclear receptor Nur77 has been shown to inhibit proliferation of vascular cells and inflammation. In addition, Nur77 has been shown to modulate TGFβ/BMP pathway in a cell-and context- dependent manner. Collectively, given the effects of Nur77 on inflammation, SMC and EC, we hypothesized that activation of Nur77 may become a promising treatment of PAH.

Methods: Primary pulmonary ECs and SMCs, lung tissue sections from control, hereditary- and idiopathic- PAH lungs, and rat models of Sugen-hypoxia and MCT-induced pulmonary hypertension (PH) were used. Immunohistochemical, quantitative PCR, western blot, luciferase reporter, ELISAs, and proliferation assays were performed. 6-Mercaptopurine (6-MP), an agonist of Nur77 has been tested in Sugen-hypoxia model of P(A)H. Lung and heart tissues were analyzed for proliferation, inflammation and BMP signalling. Furthermore, hemodynamic measurements were performed.

Results: Immunohistochemical analyses demonstrated that Nur77 is expressed in many lung cells, including ECs and SMCs. qPCR and Western blot analyses revealed that Nur77 is significantly decreased in pulmonary ECs in both iPAH and HPAH patients. Nur77 significantly increased BMP signalling through augmentation of BMPR2, Smad1/5/9 and ID1 genes. Furthermore, Nur77 exhibits strong anti-inflammatory and anti-proliferative effects in pulmonary ECs. 6-MP significantly inhibited pulmonary vascular remodeling by inhibition of EC and SMC proliferation and perivascular inflammation. Finally, 6-MP improved cardiac function by improving stroke volume and cardiac output.

Conclusions: Our data indicate that Nur77 acts as a novel negative regulator of pulmonary ECs dysfunction in PAH and therefore activation of Nur77 by 6-MP may represent a useful therapeutic strategy to treat PAH.

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