白介素21受体在肺动脉高压肺血管重构中的作用及机制

肺动脉高压（PH）是一种以肺动脉压力和阻力进行性增高为特点的致死性疾病或临床综合征。白介素21（IL-21）及其受体（IL-21R）参与了白介素6介导的缺氧性肺动脉高压，我们最近发现IL-21R在肺动脉高压患者和动物模型的肺血管内皮细胞和内皮祖细胞上的表达升高；而血管内皮细胞上的IL-21R激活后产生效应主要通过两种形式调控STAT3以实现：（1）Tyr705位的磷酸化，使STAT3入细胞核调控细胞转录；（2）Ser727位的磷酸化，使STAT3入线粒体调控细胞的糖酵解。此外，IL-21可以上调肺动脉内皮细胞的microRNA-30b，进而长效（24h）调控STAT3进入细胞核或线粒体。本项目旨在：（1）全面评估IL-21R/microRNA-30b/STAT3通路在肺血管重构中的作用及其分子机制；（2）利用动物模型和临床标本，评估调控内皮祖细胞的IL-21R能否成为治疗肺动脉高压的新途。

Pulmonary hypertension (PH) is a lethal disease or syndrome with progressive elevation of pulmonary artery pressure and resistance. Previous study demonstrated that interleukin-21 (IL-21) receptor (IL-21R) knockout resulted in lower pulmonary pressure in mouse hypoxia-induced pulmonary hypertension model. We found that IL-21R is elevated in pulmonary artery endothelial cells and endothelial progenitor cells from both PH patients and animal models. We recently reported that in endothelial cells, IL-21R activation resulted in STAT3 phosphorylation in 2 sites: (1) phosphorylation of Tyr705, which leads to STAT3 translocation to cellular nucleus and regulates gene transcription; (2) phosphorylation of Ser727, which leads to STAT3 translocation to mitochondria regulates glycolysis. In addition, we found that microRNA-30b is upregulated by IL-21 in endothelial cells, and microRNA-30b regulates STAT3 translocation to both cell nucleus and mitochondria 24 hours after transfection (long term, 24h). Taken together, this study will determine: (1) the effects and mechanisms of IL-21R/microRNA-30b/STAT3 pathway in pulmonary vascular remodeling; (2) whether modulation of IL-21R in endothelial progenitor cells could be a new therapeutic strategy for PH by using both animal model and human samples.