骨形成蛋白7激活ActRⅡa/MAPK-p38通路对肺动脉平滑肌细胞增殖及血管重构的影响

Bone Morphogenetic Proteins (BMPs) signals plays a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). In Bone Morphogenetic Protein Receptor Ⅱ (BMPRⅡ) deficient cells, preferred ligands for BMPRⅡ, such as BMP2 and BMP4, exhibit diminished signaling, whereas BMP7, a high affinity ligand for Activin Receptor Ⅱa (ActRⅡa) exhibits increased activity. Preliminary experiments in our center showed that heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH) patients have a much higher plasma BMP7 level compared with controls, whereas no differences were found in BMP2/BMP4 levels. We raise the hypothesis that excessive expression of BMP7 activates the MAPK pathway through the ActRⅡa to exert effect on the cell proliferation of PASMC. In order to further investigate the effect of BMP7 in pulmonary vasculature, we design our research in three aspects, that is the cells, the lung tissues and the clinical aspects. For the further research, we establish BMPR2 dificient human PASMC by siRNA method combined with BMP7 treatment to investigate the mechanism of BMP7 in BMPR2 dificient PASMC and the alteration of cell proliferation. In addition, we also investigate the expression of BMP7 in HPAH lung tissues. Finally, we will analyse the role and mechenism of plasma BMP7 levels in hemodynamic parameters ang survival time.

骨形成蛋白（BMPs）信号通路在肺动脉高压患者中发挥重要作用。BMPR2基因缺陷可能导致BMP2、BMP4/BMPRⅡ介导信号通路减弱，而BMP7 /活化素受体Ⅱa（ActRⅡa）介导通路增强。本课题组前期研究发现遗传性肺动脉高压患者血浆BMP7水平较对照组显著增加，而BMP2、BMP4则无差异。研究假设：过度表达的BMP7通过ActRⅡa/ MAPK-p38通路，对肺动脉平滑肌细胞增殖和血管重构产生影响。本研究从细胞学、组织学和临床分析三方面开展。通过干扰RNA构建BMPR2缺陷人肺动脉平滑肌细胞模型，给予外源性BMP7刺激，研究肺动脉平滑肌细胞增殖变化及导致这些变化的分子信号通路，进一步在遗传性肺动脉高压患者肺组织中验证BMP7表达。分析遗传性肺动脉高压和特发性肺动脉高压患者血浆BMP7水平对血流动力学和患者生存时间的影响及其机制。

本课题探究了骨形成蛋白7（BMP7）在肺动脉高压（PAH）患者和动物模型中的表达情况、功能和作用机制。课题组通过检测特发性肺动脉高压（IPAH）、遗传性肺动脉高压（HPAH）和对照者血浆BMP7水平发现HPAH和IPAH患者血浆BMP7水平显著升高，且HPAH患者更为显著，升高的血浆BMP7水平与患者不良预后相关。为进一步探究BMP7在PAH中的功能和作用机制，课题组利用PAH模型大鼠（MCT）和肺动脉平滑肌细胞（PASMC）开展了系列研究工作。在人 PASMC 中利用 BMPR2 干扰RNA模拟 BMPR2基因缺陷模型，探究 BMP7 在 BMPR2 缺陷的人PASMC 中的作用，同时给予MCTP和外源性BMP7处理PASMC，并进一步探索其发挥作用的机制，结果提示高表达的BMP7主要是通过与活化素受体2A结合并激活下游MAPK-p38通路，引起细胞周期蛋白改变，进而影响PASMC的增殖和血管重构。