PRDX6调控肺动脉内皮细胞铁死亡激活NRLP3炎性小体在肺动脉高压的作用机制研究

肺动脉高压(Pulmonary hypertension, PH)是一种多因素引起的肺血管阻力进行性增高，最终导致右心衰竭和死亡的心肺血管临床综合征。然而，其作用机制尚未明确。我们前期研究表明，野百合碱诱导PH大鼠肺动脉内皮细胞（PAECs）铁死亡参与肺血管重构，PRDX6下调表达与PAECs铁死亡密切相关；PAECs铁死亡参与肺血管重构可能与调控HMGB1/TLR4通路继而活化NLRP3炎性小体有关。因此，本课题拟建立MCT诱导及缺氧联合SU5416诱导PH大鼠两种模型，以验证PH的PAECs铁死亡情况，并利用siRNA、目的基因过表达慢病毒载体、基因导入、细胞形态分析、ROS检测、激光共聚集等技术，检测肺动脉内皮细胞铁死亡程度，以阐明PRDX6对肺动脉内皮细胞铁死亡的调控作用及铁死亡激活NRLP3炎性小体参与肺血管重构的分子机制，为PH的防治提供理论依据和寻找有效的干预靶点。

Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right-sided heart failure associated with significant morbidity and mortality. However, the molecular mechanism remains elusive. Our previous experimental evidences indicate that ferroptosis of pulmonary artery endothelium cells (PAECs) is involve in the progression of PH in monocrotaline induced rats. Moreover, downregulated PRDX6 has closed relation with ferroptosis of PAECs. Ferroptosis of PAECs involved in pulmonary vascular remodeling may be related to the upregulation of HMGB1/ TLR4 pathway and then activation of NLRP3 inflammasome. Therefore, we 1) study ferroptosis of PAECs in MCT induced and hypoxia + SU5416 induced model of PH in vivo, and PAECs from the rats in vitro; 2) investigate PRDX6 involve in ferroptosis regulation in PH rats by siRNA, target gene overexpression with lentiviral vector, gene introduction, analysis of cell morphology, iron levels and reactive oxygen species (ROS) detection; 3)elucidate the molecular mechanisms of PAECs ferroptosis involve in PH via HMGB1/TLR4 pathway and thus NRLP3 inflammasome activation. These basic studies aim to provide a theoretical basis for the prevention and treatment of PH patients and develop mechanism-based effective therapeutic trategies.