State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Acta Physiol (Oxf). 2019 Jul;226(3):e13263. doi: 10.1111/apha.13263. Epub 2019 Feb 27.
Proteins mainly expressed in normal lungs and significantly changed in lungs exposed to systemic-to-pulmonary shunts might be promising targets for pulmonary arterial hypertension induced by congenital heart diseases (PAH/CHD). This study aimed to investigate the potential role of differential screening-selected gene aberrative in neuroblastoma (DAN) in PAH/CHD.
PAH was surgically induced by the combined surgery (right pulmonary artery ligation and left cervical systemic-to-pulmonary shunt) in Sprague-Dawley (SD) rats. Exogenous DAN was supplemented by osmotic minipumps.
Firstly, DAN was significantly decreased in patients with severe PAH/CHD and negatively correlated with pulmonary hemodynamic indices derived from right cardiac catheterization. Secondly, pulmonary hypertensive status and apparent pulmonary vasculopathies of PAH/CHD were surgically reproduced in SD rats. Real time-PCR and Western blot analysis revealed that DAN mRNA and protein levels decreased in lungs exposed to systemic-to-pulmonary shunts, and immunofluorescence staining found that DAN was highly expressed in pulmonary arteries of normal lungs but seldom detected in severely remodelling pulmonary arteries, furthermore, plasma levels of DAN in shunted-rats manifested a time-depended decrease and negatively correlated with pulmonary hemodynamic indices. Thirdly, DAN specially reversed the anti-proliferative and pro-apoptotic effects of bone morphogenetic protein 2/4 (BMP2/4) on pulmonary arterial smooth muscle cells via BMP2/4-BMPR2-Smad1/5/8-Id1 signalling pathway. Furthermore, continuous supplementation of exogenous DAN protein increased the extent of shunt-associated PAH.
Compensatory decrease of DAN in hypertensive lungs may retard the deterioration of shunt-associated PAH, at least in part, by antagonizing BMP signalling pathway. Furthermore, DAN might be a potential biomarker for PAH/CHD.
主要在正常肺组织中表达且在肺暴露于体肺分流时明显改变的蛋白质可能是先天性心脏病（CHD）相关肺动脉高压（PAH）的有前途的治疗靶点。本研究旨在探讨差异筛选选择基因异常在神经母细胞瘤（DAN）中的潜在作用在先天性心脏病相关肺动脉高压（PAH/CHD）中。
通过右肺动脉结扎和左颈总动脉至肺动脉分流联合手术在 Sprague-Dawley（SD）大鼠中诱导 PAH。通过渗透微型泵补充外源性 DAN。
首先，严重 PAH/CHD 患者的 DAN 明显减少，与右心导管检查得出的肺血流动力学指标呈负相关。其次，SD 大鼠成功复制了 PAH/CHD 的肺动脉高压状态和明显的肺血管病变。实时 PCR 和 Western blot 分析显示，DAN mRNA 和蛋白水平在体肺分流肺中降低，免疫荧光染色发现 DAN 在正常肺的肺动脉中高表达，但在严重重塑的肺动脉中很少检测到，此外，分流大鼠的 DAN 血浆水平表现出时间依赖性下降，与肺血流动力学指标呈负相关。第三，DAN 通过 BMP2/4-BMPR2-Smad1/5/8-Id1 信号通路特异性逆转骨形态发生蛋白 2/4（BMP2/4）对肺动脉平滑肌细胞的抗增殖和促凋亡作用。此外，持续补充外源性 DAN 蛋白增加了分流相关 PAH 的程度。
高血压肺中 DAN 的代偿性减少可能通过拮抗 BMP 信号通路至少部分减缓分流相关 PAH 的恶化。此外，DAN 可能是 PAH/CHD 的潜在生物标志物。
