Abstract：
Nur77 is a member of the NR4A subfamily of orphan nuclear receptors that is expressed and has a function within the immune system. This study aimed to investigate the role of Nur77 in hypoxic pulmonary hypertension. SPF male SD rats were exposed in hypobaric chamber simulating 5000 m high altitude for 0, 3, 7, 14, 21 or 28 days. Rat pulmonary artery smooth muscle cells (RPASMCs) were cultured under normoxic conditions (5% CO2-95% ambient air) or hypoxic conditions (5% O2 for 6 h, 12 h, 24 h, 48 h). Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased pulmonary arterial pressure. The levels of Nur77, HIF-1α and PNCA were upregulated in pulmonary arterial smooth muscle from hypoxic rats. Silencing of either Nur77 or HIF-1α attenuated hypoxia-induced proliferation. Silencing of HIF-1α down-regulated Nur77 protein level, but Nur77 silence did not reduce HIF-1α. Nur77 was not con-immunoprecipitated with HIF-1α. This study demonstrated that Nur77 acted as a downstream regulator of HIF-1α under hypoxia, and plays a critical role in the hypoxia-induced pulmonary vascular remodeling, which is regulated by HIF-1α. Nur77 maybe a novel target of HPH therapy.
摘要：
Nur77是孤儿核受体NR4A亚家族的成员，在免疫系统中表达并具有功能。本研究旨在探讨Nur77在缺氧性肺动脉高压中的作用。SPF雄性SD大鼠在模拟5000m高海拔的低压舱中暴露0、3、7、14、21或28天。大鼠肺动脉平滑肌细胞（RPASMC）在常氧条件下（5％CO2-95％环境空气）或低氧条件下（5％O2持续6小时，12h,24h,48小时)。低氧大鼠发生肺动脉重构和右心室肥厚，肺动脉压明显升高。低氧大鼠肺动脉平滑肌中Nur77、HIF-1α和PNCA水平上调。沉默Nur77或HIF-1α可减弱缺氧诱导的增殖。沉默HIF-1α下调Nur77蛋白水平,但Nur77沉默并没有降低HIF-1α。Nur77未与HIF-1α免疫沉淀。这项研究表明，Nur77在缺氧下充当HIF-1α的下游调节因子，并在缺氧诱导的肺血管重塑中起关键作用，受HIF-1α调节。Nur77可能是HPH治疗的新靶点。
