缺氧诱生因子-1α（HIF-1α）影响先天性心脏病所致肺动脉高压发展的机制研究

我们前期研究发现肺动脉血氧饱和度增高对肺高压具有保护作用：虽然都存在左向右分流，但大动脉转位（TGA）患者肺动脉发自左心室，因此其肺动脉血氧饱和度明显高于室间隔缺损（VSD）患者，且TGA组术前肺组织MMP-2表达明显低于VSD组，使其肺血管重构及术后肺动脉压下降程度优于VSD组。但肺动脉血氧饱和度增高调控MMP-2的机制尚不清楚，因此结合文献提出研究假设：肺动脉血氧饱和度增高，增加HIF-1α灭活，减少血管紧张素II及内皮素I表达，进而影响RhoA/ROCK系统，减少MMP-2生成，改善肺血管重构。计划建立肺动脉血氧饱和度梯度变化的肺高压模型，通过检测上述因子表达是否也呈梯度变化，从微观角度评价血氧饱和度的影响；通过检测肺动脉的膨胀性，宏观评价肺动脉重构情况；通过加入HIF-1α抑制剂，逆向验证HIF-1α是否为关键调控因子，并检验其能否模拟血氧饱和度增高的保护作用，为研发药物奠定基础。

Our previous studies have shown that an increase of pulmonary arterial oxygen saturation acts as a protection factor for the pulmonary hypertension. A left-to-right shunt exists both in the patients with transposition of the great arteries (TGA) associated with ventricular septal defect (VSD) and the patients with VSD. Because the pulmonary artery connects with the left ventricle, the former have significantly higher pulmonary arterial oxygen saturation than the latter. Moreover, before the operation, the matrix metalloproteinase 2 (MMP-2) in pulmonary tissue in patients with TGA is significantly lower than that in patients with VSD, which is beneficial to reduce the pulmonary vascular remodeling and to decrease the pulmonary artery pressure after operation. However, the mechanism how the increase of pulmonary arterial oxygen saturation reduces the MMP-2 expression is unclear. Leading to the hypothesis that the increase of pulmonary artery oxygen saturation promote the inactivation of the hypoxia inducible factor-1α (HIF-1α) and reduce the expression of the angiotensin II and endothelin I, eventually improve the remodeling of the pulmonary artery by influence the RhoA / ROCK signaling pathway and reduce the MMP-2 expression. A model of pulmonary hypertension including a series of pulmonary artery oxygen saturation will be established to investigate whether the expression of the key factors such as HIF-1α, RhoA / ROCK signaling pathway and MMP-2 would be changed according to the different pulmonary artery oxygen saturation. Meanwhile, the video monitor will be used to display the expansion of the pulmonary artery in the model and then evaluate the remodeling of the pulmonary artery. At the same time, HIF-1α inhibitor will be added to the same model to confirm whether the HIF-1α is a key factor in the regulation process, and to verify whether the increase of pulmonary arterial oxygen saturation act as protection factor for the pulmonary hypertension after inhibit the HIF-1α, in order to establish the foundation for research of new drugs.