骨形成蛋白7调控肺动脉高压肺血管重构的表观遗传学机制

Pulmonary arterial hypertension(PAH) is a rare clinical disease, the pathogenesis of which remains unclear. Bone morphogenetic protein (BMP) signal plays a significant role in the development of PAH. Our center has found that the plasma levels of BMP7 are dramatically higher compared to controls, which could also applied to the lung tissue of PAH model (MCT) rat. The abnormal elevated BMP7 increase the proliferation and migration of pulmonary artery smooth muscle cells.These results indicate that BMP7 may participate in the pulmonary vascular remodeling and the development of PAH. We also detect that BMP7 expression levels may regulated by methylation of DNA, though little is known about the similarities and difference in regulatory mechanism that control BMP7 expression. Based on above data, we explore the regulation of DNA methylation effect and the underlying molecular mechanisms of BMP7 in vivo and in vitro, as well as the effect of BMP7 on pulmonary vascular remodeling and prognosis significance in pulmonary arterial hypertension. BMP7 may become a promising target of PAH, which may help illustrate the development of PAH and provide potential targets for drug intervention.

肺动脉高压（PAH）是一种临床罕见病，其发病机制尚未完全阐明。骨形成蛋白（BMP）信号通路是参与PAH发生发展的重要通路之一。我中心前期工作发现，PAH患者血浆BMP7水平较对照组显著升高，且在野百合碱诱导的PAH模型大鼠肺组织中BMP7表达水平也显著高于对照大鼠；异常升高的BMP7增强肺动脉平滑肌细胞的增殖和迁移能力，这表明BMP7可能参与肺血管重构和PAH的发生发展。我们前期研究还证实了BMP7的表达水平受DNA甲基化调控，但是PAH患者的调控机制是否存在异同仍未知。基于此，本研究从体内体外水平探究肺动脉高压致病因素作用下表观遗传学BMP7基因表达调控的影响及相应分子机制，以及高表达的BMP7对PAH肺血管重构的影响，进一步评估其与患者不良预后的相关性。BMP7有望成为PAH新靶点，为探究PAH的发生发展提供新思路，为药物干预提供潜在靶点。

课题组前期工作发现在肺动脉高压（Pulmonary arterial hypertension，PAH）患者血浆中骨形态发生蛋白7（Bone morphogenetic protein 7，BMP7）表达升高，且升高的BMP7与患者不良预后相关，其分子机制为升高的BMP7通过ACTR2A/p38 MAPK信号通路促进肺动脉平滑肌细胞（Pulmonary artery smooth muscle cells，PASMC）增殖，进而引起肺血管重构；基于上述研究背景，本课题主要探讨肺动脉高压肺血管重构中BMP7表达的表观遗传学机制。首先，课题组从体外和体内水平明确BMP7在PH模型中表达升高，且升高的BMP7显著促进PASMC的增殖；其次，通过药物干预DNA甲基化和组蛋白乙酰化修饰发现，BMP7的表达受表观遗传机制调控，进一步利用生物信息学方法预测发现BMP7启动子区存在2个CpG岛，分子实验检测发现DNA甲基化转移酶1（DNA methyltransferase 1，DNMT1）在PH模型中表达降低，具体机制为DNMT1通过调节BMP7启动子区DNA甲基化修饰水平调控其表达；最后，选取PAH患者和对照组全血进行DNA甲基化芯片检测，发现PAH患者BMP7启动子区DNA甲基化修饰水平显著低于对照组，并对低甲基化差异表达基因进行GO和KEGG分析，显示其显著富集于细胞外基质结构、活性氧生物合成及血管收缩等生物过程。本研究从DNA甲基化修饰角度揭示BMP7升高的表观遗传调控机制，为PAH临床转化治疗提供了一个全新的和潜在的干预靶点。目前课题组已发表标注项目基金号SCI论文5篇，其中通讯作者4篇，影响影子大于5分2篇；在投文章2篇。