PDGFBB-MAPK调节MMP:TIMPs的平衡参与BAV主动脉瘤的形成

VSMCs play a key role in the pathological process of ascending thoracic aortic aneurysm (ATAA) induced by bicuspid aortic valve (BAV). It is a crucial step that the ECM structural change caused by MMP: TIMPs imbalance. But signal transduction pathway and molecular mechanism of aortic VSMCs degeneration and dysfunction are still not clear in the ATAA induced by BAV. Based on bioinformatics analysis of gene microarray data, we found that PDGFBB-MAPK may be an important pathway participated in BAV inducing ATAA. It was found that the expression of PDGFBB in ATAA was increased compared with normal aorta. Furthermore, the expression of miR-17 family members were increased after PDGFBB treatment in aortic primary cultured VSMCs. We hypothesis that PDGFBB activates the MAPK pathway of VSMCs by autocrine or paracrine, and then cause the effects as followed: increase the expression of miR-17 family members, which inhibit its target molecule TIMP1/2 and lead to MMPs activity increased; increase the expression level of MMPs, thus contribute to the imbalance of MMP: TIMPs; and regulate the expression of some molecules that promote aneurysm in the phenotypic transformation of VSMCs. Summarily, PDGFBB promotes the development and process of ATAA. This study provides a theoretical basis and a new perspective for ATAA induced by BAV.

BAV导致的ATAA形成过程中VSMCs起着核心作用，MMP：TIMPs比例失衡导致的ECM结构改变是关键的环节之一，但导致主动脉VSMCs退变、细胞功能不全的信号转导通路、分子机制依然不清。我们通过基因芯片和生物信息学分析发现PDGFBB-MAPK可能是一个重要的参与BAV导致的ATAA的通路。前期工作发现对比正常主动脉，ATAA的PDGFBB表达增高，并且用PDGFBB处理升主动脉VSMCs可以导致而miR-17家族的表达增高。我们推测PDGFBB通过自分泌或旁分泌激活VSMCs MAPK通路，引起以下作用：增加miR-17家族成员的表达，抑制其靶分子TIMP1/2，促使MMPs活性增加；增加MMPs的表达水平，为MMP：TIMPs失衡起到贡献；在VSMCs的表型转化中起到作用，调控一些促进主动脉扩张的分子的表达。综上，促进ATAA的发生发展过程。本研究为BAV相关ATAA机制提供新的视角。

BAV导致的ATAA形成过程中VSMCs起着核心作用，MMP：TIMPs比例失衡导致的ECM结构改变是关键的环节之一，但导致主动脉VSMCs退变、细胞功能不全的分子机制依然不清。.利用临床样本，我们分别把BAV和marfan主动脉严重扩张和轻度扩张组织进行对比，发现miR-17家族成员表达和TIMPs的表达，MMP2的表达和活性趋势一致，但MMP9的表达趋势有差异。为进一步揭示BAV和TAV个体主动脉扩张组织的形成机制不同，我们利用相关GEO数据集进行深度生信分析，通过WGCNA分析发现TAA/BAV和TAA/TAV的致病机制存在关键免疫相关细胞的激活模式和一些免疫相关基因表达的差异。.针对细胞功能学内容部分，为获得更准确和更有价值的信息，我们对PDGFBB处理HAVSMC细胞进行了RNA测序和microRNA测序，通过对测序的数据进行差异基因和ceRNA分析，围绕TIMPs/MMPs平衡，提炼出相关lncRNAGAS5及相关miRNA进行进一步功能研究。我们发现PDGFBB处理HAVSMC细胞后，miRNA-17家族成员表达量多数增高，这为TIMP2的降低起到了作用；明星分子lncRNAGAS5也可以结合miRNA-429降低TIMP2的表达水平，从而影响TIMPs/MMPs的平衡。并且进一步研究发现lncRNA GAS5/miR-137/MEF2A反馈调节轴参与PDGFBB引起的HAVSMC增殖和表型转换等细胞生物学过程。以上研究结果可为主动脉类心血管疾病的临床治疗现状提供理论基础和新的靶向治疗策略。.得益于本课题的经费资助，我们已取得了关键的实验结果，部分相关文章已发表，还有重要结果正在投稿中。同时培养了数名优秀的研究生。