Abstract 9797: Nur77 Inhibits Pulmonary Artery Smooth Muscle Cell Proliferation Though Targeting the STAT3/Pim-1/NFAT Axis

Abstract

The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in cardiovascular system. However, the molecular mechanism underlying the regulation of NR4A receptor expression and its functional significance in pulmonary artery smooth muscle cell (PASMC) proliferation remain unclear. Here we investigated whether NR4A family regulates PASMC proliferation, and if so, to determine the mechanism involved. By using quantitative real-time PCR (qRT-PCR), we showed that orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared to other two members, NOR-1 and Nurr1. In rat PASMCs, the expression of Nur77 was robustly induced in response to several pathologic stimuli implicated in pulmonary artery hypertension (PAH), such as hypoxia, 5-hydroxytryptamine (5-HT), platelet derived growth factor (PDGF), and endothelin-1. Importantly, the protein levels of Nur77 are significantly increased in the lungs of monocrotaline (MCT) induced PAH rats. Furthermore, we demonstrated that 5-HT, a potent mitogen for PASMC, markedly up-regulated the Nur77 expression, through mitogen activated protein kinases/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway in rat PASMCs. Overexpression of Nur77 markedly inhibited 5-HT induced cell proliferation, and the expression of Cyclin D1 and proliferating cell nuclear antigen (PCNA) in rat PASMCs. Moreover, knockdown of Nur77 augments the 5-HT induced PASMC proliferation. Mechanistically, we demonstrated that Nur77 specifically interacts with STAT3, thus inhibiting its phosphorylation and the expression of its target genes, such as Pim-1, NFATc2, and survivin in PASMCs, which are critical for the PASMC proliferation and the development of PAH. These results indicate that Nur77 is a novel negative regulator for PASMC proliferation through inhibiting the STAT3/Pim-1/NFAT axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH.