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