BMP信号通路介导的铁代谢调节在肺动脉高压中的作用

肺动脉高压（PAH）是心血管疾病防治的一大难题。近年研究发现，铁缺乏参与低氧性肺高压发生发展，也普遍存在于特发型患者，补铁可改善其症状，提示铁在PAH发病中扮演重要角色。但是铁缺乏的原因及如何参与PAH进程尚不清楚。已知hepcidin是铁代谢调节的关键蛋白，其表达受骨形成蛋白（BMP）调控，后者正是PAH关键蛋白之一。预实验发现PAH大鼠肝脏BMP6和hepicidin表达显著上调。因此，我们推测PAH时BMP信号通路通过上调hepcidin而引起铁缺乏。此外，铁具有较强的氧化还原活性，在调节血管内皮功能中具有重要作用。我们推测，铁缺乏可造成肺血管内皮氧化应激水平升高，功能受损，引起PAH。本研究着眼于铁代谢的上下游，从细胞分子、血管组织及整体动物水平研究BMP信号通路对铁代谢的调节机制及铁缺乏对肺血管内皮功能的影响，力求阐明PAH铁代谢紊乱的机制，为补铁治疗新策略提供理论依据。

Pulmonary arterial hypertension is a serious disease with poor prognosis and high mortality. Recent research reveals that iron deficiency is highly associated with PAH and iron supplement could improve the symptom of PAH. But the role and regulatory mechanism of iron deficiency in PAH remains unclear. It is well known that hepcidin is a key regulator of iron metabolism which is specifically synthesized in liver. The expression of hepcidin is mainly controlled by BMP/BMPR-II/Smad signaling pathway, which plays a critical role in PAH. Our previous study found that BMP6 and hepcidin were up-regulated in liver under hypoxia, which aroused our interest to investigate whether BMP signaling pathway regulate iron metabolism via hepcidin pathway. Meanwhile, previous researches have revealed the REDOX activity of iron, which can also induce oxidative stress and regulate endothelial function to participate in the development of cardiovascular disease. We assume that iron regulates endothelial function and pulmonary vasoconstriction through oxidative stress modulation. The present study focuses on the upstream and downstream mechanism of iron metabolism, aiming to clarify the regulatory effect of BMP signaling pathway on iron metabolism and its implication in PAH. This project will help to reveal the mechanism of iron disorder in PAH and provide theoretical basis for iron supplement therapy in PAH.