miR-663通过靶向TGF-β1/GDF11-SMAD通路调控肺动脉高压中肺动脉和右心室重构

miRNAs play important roles in regulation of PAH, but whether there is a miRNA that highly efficiently regulates the disease is still unclear. Our group found that miR-663 regulates VSMC phenotypic switch by targeting JunB/Myl9. The primary study of this project indicated lacking of the expression of miR-663 in human PAH pulmonary arterial smooth muscle cells. Moreover, miR-663 inhibited both PDGF and hypoxia induced hPASMC proliferation and migration through targeting TGF-β1 and GDF11. The proposed study is to investigate the role of miR-663 in regulation of TGF-β1/GDF11-SMAD pathway and hPASMC phenotypic switch, including contractile markers expression, proliferation, migration, apoptosis and collagen synthesis.The regulation of miR-663 on hPASMC secreted TGF-β1 and GDF11 will be studied, as well as its indirect effects on hPAEC proliferation, migration and apoptosis. Lentivirus-miR-663 or agomiR-663 will be delivered systemically or locally into rodent PAH models. The expression efficiency will be analyzed in pulmonary arteries. Remodeling of pulmonary artery and right ventricle will be investigated. The results of the study may help to develop novel therapies for the treatment of PAH.

miRNA在肺动脉高压(PAH)的发病中起重要作用，但目前尚未有高效调控PAH的miRNA报道。本课题组在发现miR-663通过靶向JunB/Myl9调控主动脉平滑肌细胞表型转化的基础上进一步研究首次发现，miR-663在人PAH肺动脉平滑肌表达量降低并能调控PDGF和缺氧诱导的hPASMC增殖和迁移，TGF-β1和GDF11为miR-663的靶基因。因此miR-663可能通过靶向TGF-β1/GDF11-SMAD通路调控PAH的发生。本项目拟深入研究miR-663通过该途径对hPASMC表型调控的机制；miR-663对hPASMC分泌TGF-β1和GDF11的调控及其对内皮细胞表型的间接影响。采用局部和整体导入的方式比较lenti-miR663和agomiR-663在PAH模型肺动脉中膜的表达效率并评价其对肺动脉和右心室重构的调控。结果有望为开发新的PAH靶向治疗手段提供有价值的线索。

miRNA在肺动脉高压(PAH)的发病中起重要作用，但目前尚未有高效调控PAH的miRNA报道。本课题组在发现miR-663通过靶向JunB/Myl9调控主动脉平滑肌细胞表型转化的基础上进一步研究首次发现，miR-663在人PAH肺动脉平滑肌表达量降低并能调控PDGF和缺氧诱导的hPASMC增殖和迁移，TGF-β1为miR-663的靶基因。因此miR-663可能通过靶向TGF-β1/ SMAD通路调控PAH的发生。项目按照计划完成了全部研究内容，包括miR-663在人肺动脉高压中的表达；PDGF-BB刺激人肺动脉平滑肌细胞miR-633的表达变化；miR-663介导 PDGF-BB刺激下人肺动脉平滑肌细胞增殖、迁移的变化；腺病毒介导的miR-663过表达能够抑制MCT诱导大鼠肺动脉重构；确定TGF-β1是miR-663的靶基因；miR-663调控PDGF-BB诱导的Smad磷酸化；miR-663调控PDGF-BB诱导的血管平滑肌细胞纤维化；miR-663能够抑制MCT诱导的肺动脉高压大鼠肺动脉压力、右心室压力和右心系统的重构。结果有望为开发新的PAH靶向治疗手段提供有价值的线索。