慢性血栓栓塞性肺动脉高压肺血管重构的miRNAs调控机制

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition characterized by single or recurrent pulmonary thromboemboli, which promoting increased pulmonary vascular resistance and progressive pulmonary hypertension and right-heart failure.The elevated pulmonary artery pressure in CTEPH patients arises not only from central pulmonary vessels obstruction, but from the development of remodeling in small pulmonary arteries. It has been demonstrated that regulation of miRNAs plays an important role in the pathogenesis of cardiovascular disease related to the heart and vascular remodeling including hypoxia induced pulmonary hypertension. The aim of this study is to investigate the relationship between the miRNAs and the pathogenesis of CTEPH. ① To compare the difference of miRNAs expression profile between CTEPH patients and normal people, ② Based on the miRNAs' target gene prediction, functional analysis and pathway analysis, try to reveal the role of miRNAs in the pathogenesis of CTEPH. ③ Try to find a biomarker from the differently expressed miRNAs for the prediction of CTEPH and its post-operative outcomes. The results of this study would provide us a novel therapy target for treating the patients with CTEPH.

慢性血栓栓塞性肺动脉高压（CTEPH）发病隐匿、进展迅速、死亡率高。尽管一直认为其发生与栓子对中心肺动脉的阻塞有关，但大量临床资料提示肺血管重构可能是影响其发展与预后的关键。miRNAs是真核细胞中内源性单链小调节RNA的一种，在转录后水平调节基因的表达和细胞行为。我们前期研究结果证实miRNAs对低氧性肺动脉高压肺血管重构具有重要调节作用。本研究在此基础上进一步探讨miRNAs在CTEPH 肺血管重构中的作用。①比较验证正常对照组与CTEPH患者外周循环及平滑肌细胞miRNA的表达谱差异；②分析其与CTEPH疾病发生及预后的关系；③探讨关键差异基因在肺血管重构中的功能作用；④研究其作用的下游靶基因和信号通路；⑤观察抑制该通路各个环节对肺血管重构的影响。通过该研究，以期阐明CTEPH患者肺血管重构的miRNAs调控作用与机制，为CTEPH的筛查、预防与治疗提供新靶点。

慢性血栓栓塞性肺动脉高压（CTEPH）发病隐匿、进展迅速、死亡率高。尽管一直认为其发生与栓子对中心肺动脉的阻塞有关，但大量临床资料提示肺血管重构可能是影响其发展与预后的关键。miRNAs是真核细胞中内源性单链小调节RNA的一种，在转录后水平调节基因的表达和细胞行为。我们前期研究结果证实miRNAs对低氧性肺动脉高压肺血管重构具有重要调节作用。本研究中①比较了正常对照组与CTEPH患者外周循环及平滑肌细胞miRNA的表达谱差异；发现let-7b可用于辅助CTEPH的诊断，而let-7d在CTEPH中表达水平下调②分析其与CTEPH疾病发生及预后的关系，发现其病人血浆ET-1水平与let-7b水平呈中度负相关；let-7b敲减的PAEC细胞株，采用siRNA沉默TGFBR1表达后，可逆转let-7b下调引起的ET-1水平的升高。采用let-7d mimics转染PASMC，p21表达上调，从而抑制PASMC的增殖。通过该研究，发现CTEPH患者肺血管重构的miRNAs调控作用及机制，为CTEPH的筛查、预防与治疗提供新靶点。