DAN plays important compensatory roles in systemic-to-pulmonary shunt associated pulmonary arterial hypertension
DAN plays important compensatory roles in systemic-to-pulmonary shunt associated pulmonary arterial hypertension
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DAN 在体肺分流相关的肺动脉高压中发挥重要的代偿作用
DOI：
10.1111/apha.13263
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发表时间：
2019-07-01
影响因子：
6.3
通讯作者：
Hu, Shengshou
中科院分区：
文献类型：
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作者：
Meng, Liukun;Liu, Xiaoyan;Hu, Shengshou
目的研究主要表达于正常肺组织，而在体肺分流肺组织中表达显著改变的蛋白质，为先天性心脏病肺动脉高压（PAH/CHD）的治疗提供新的靶点。本研究旨在探讨PAH/CHD患者神经母细胞瘤（DAN）中差异筛选选择性基因异常的潜在作用。方法采用右肺动脉结扎+左颈体肺分流术联合手术建立SD大鼠肺动脉高压模型。通过渗透微泵补充外源DAN。结果1.重度PAH/CHD患者DAN明显降低，与右心导管肺血流动力学指标呈负相关。其次，在SD大鼠中手术复制PAH/CHD的肺动脉高压状态和明显的肺血管病变。真实的time-PCR和Western blot分析显示，体肺分流大鼠肺组织中DAN mRNA和蛋白水平均降低，免疫荧光染色显示DAN在正常肺动脉中表达增高，而在严重重构肺动脉中很少检测到DAN的表达，并且DAN在分流大鼠血浆中的水平呈时间依赖性降低，与肺血流动力学指标呈负相关。第三，DAN通过BMP 2/4-BMPR 2-Smad 1/5/8-Id 1信号通路特异性逆转BMP 2/4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蛋白会增加分流相关多环芳烃的程度。结论高血压肺组织DAN代偿性减少可能通过拮抗BMP信号通路而延缓分流相关PAH的恶化。DAN可能是PAH/CHD的潜在生物标志物。
Aim 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. Methods 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. Results 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. Conclusion 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.