黑色素瘤细胞粘附分子（Mel-CAM）在体-肺分流性肺动脉高压肺血管重构中的作用机制

Researches confirmed that pulmonary vascular remodeling induced by phenotype transition of pulmonary arterial smooth muscle cells underlies the genesis of pulmonary arterial hypertension (PAH). Through an antibody microarray procedure, we found that the plasma levels of Mel-CAM were significantly up-regulated in patients with PAH/CHD, furthermore, immunohistochemistry also confirmed that Mel-CAM demonstrated a conspicuous augmentation in the remodeled pulmonary vessels in lungs from patients with irreversible PAH/CHD. Mel-CAM has been verified its involvement into the phenotype transition of cells. Therefore, we proposed that Mel-CAM is possibly involved into the genesis and/or the progression of PAH/CHD through phenotype transition of pulmonary arterial smooth muscle cells. This study attempts to further investigate：①the expression level alteration of Mel-CAM in lung tissues exposed to systemic-to-pulmonary shunt, and the correlation between the plasma level of Mel-CAM and pulmonary hemodynamic indices and the extent of pulmonary vasculopathy. ②the impacts of Mel-CAM on the proliferation, migration, apoptosis of pulmonary vascular cells and the noncanonical pathway. ③the effects of knocking-out the endogenous Mel-CAM on the progression of PAH induced by systemic-to-pulmonary shunt. Conclusively, this study aims to investigate the mechanism of Mel-CAM involved into the pulmonary arterioles remodeling process and the feasibility of Mel-CAM to be a potential treatment target for PAH/CHD.

研究证实肺动脉平滑肌细胞细胞表型改变导致的肺血管重构是肺动脉高压形成的基础。本研究通过蛋白抗体芯片筛选发现先天性心脏病相关肺动脉高压（PAH/CHD）患者外周血中Mel-CAM浓度升高显著；免疫组织化学显示不可逆性PAH/CHD重构的肺血管中Mel-CAM显著升高；研究证实Mel-CAM参与多种细胞表型的转换，因此我们推测Mel-CAM通过参与肺动脉平滑肌细胞的表型转换参与PAH/CHD形成。本项目拟阐明： ①在体-肺分流刺激下，肺组织Mel-CAM表达水平变化及其血浆浓度与肺血流动力学指标和肺血管重构程度的相关性；②Mel-CAM对肺血管细胞增殖、迁移、凋亡及信号通路的影响；③敲除Mel-CAM基因对体-肺分流性PAH的影响。本项目拟明确Mel-CAM参与PAH/CHD肺血管重构的机制及其作为潜在治疗靶点的可行性。

背景及目的：.肺动脉平滑肌细胞细胞表型改变导致的肺血管重构是肺动脉高压形成的基础，本研究通过蛋白抗体芯片筛选发现先天性心脏病相关肺动脉高压（PAH/CHD）患者外周血中Mel-CAM浓度升高显著；研究证实Mel-CAM参与多种细胞表型的转换，因此我们推测Mel-CAM通过参与肺动脉平滑肌细胞的表型转换参与PAH/CHD形成。.研究结果：.本研究中，我们成功构建一种新型体-肺分流性肺动脉高压大鼠模型，结果显示 Mel-CAM蛋白在该模型肺组织中的表达水平呈体-肺分流时间依赖性升高，而免疫组化染色显示在大鼠正常肺组织中肺小动脉仅微量表达Mel-CAM，而在体-肺分流的肺组织中严重重构的肺小动脉显著表达Mel-CAM。体外细胞实验显示Mel-CAM具有促进肺动脉平滑肌细胞增殖、迁移和凋亡抵抗的作用，同时阐明了Mel-CAM可能通过激活ERK1/2、Akt信号通路和非经典Wnt信号通路，促进肺动脉平滑肌细胞的表型转换。.结论：.Mel-CAM通过促进肺动脉平滑肌细胞增殖、迁移和凋亡抵抗而在肺动脉高压肺血管重构中发挥着重要作用，为寻找肺动脉高压新的治疗靶点提供理论依据。