miR143/145-MDM2-p53 反馈环失衡在VSMCs表型转化及主动脉中层退行性变中的机制

Given the pathogenesis of aortic media degeneration (AMD) remains unclear, it is urgently necessary to further research. Recent studies have suggested that disruption of miR143/145-MDM2-p53 feedback loop which can affect tumor vascular smooth muscle cells (VSMCs) phenotypic differentiation, regulates the cellular proliferation and apoptosis of VSMCs. Our previous study has demonstrated that the aortic tissues from aortic dissection (AD) and aortic aneurysm (AA) had significantly decreased expression of miR143/145, and VSMCs phenotypic differentiation is the initial lesion in AMD, consequently, we hypothesize that the disruption of miR143/145-MDM2-p53 feedback loop is the crucial molecular mechanism of AMD. Our program takes aortic tissues of AMD patients, nomal human VSMCs and mouse model of AMD as object of study to observe the expression, distribution and activity of each node of miR-143/145-MDM2-p53 feedback loop under physiological and pathological conditions in VSMCs, as well as to investigate the molecular mechanisms of miR-143/145-MDM2-p53 feedback loop in VSMCs phenotypic differentiation and AMD by analyzing clinical specimen, editing gene and utilizing molecular biological methods and transgenic animal model, so as to provide novel target for the prevention and treatment of AMD.

主动脉中层退行性变（AMD）的发病机制尚不明确，亟待深入研究。研究显示：miR-143/145-MDM2-P53反馈环紊乱影响肿瘤血管平滑肌细胞（VSMCs）表型转化，共同调控肿瘤VSMCs的增殖与凋亡。我们前期研究发现主动脉夹层、主动脉瘤的主动脉壁中miR-143/145表达均明显下调，而VSMCs表型转化是AMD 的先导病变。由此我们设想miR-143/145-MDM2-p53反馈环的紊乱也可能是AMD的重要分子机制。本项目旨在AMD病人主动脉组织、人主动脉VSMCs及小鼠实验性AMD模型，通过临床标本检测、基因编辑、分子生物学实验及转基因动物实验，观察miR-143/145-MDM2-p53反馈环各节点在VSMCs生理及病理状态下表达、分布及活性改变的特征，探讨miR-143/145-MDM2-p53反馈环在VSMC表型转化及AMD中的分子机制，为AMD的防治提供新的干预靶点。

目的：探讨 miR-143/145-MDM2-p53反馈环在血管平滑肌细胞（VSMC）表型转化及主动脉中膜退行性变（AMD）中的分子机制，为 AMD 的防治提供新思路。方法：在AMD的病人主动脉组织、人主动脉VSMC 及小鼠实验性 AMD 模型，通过临床标本检测、基因编辑和分子生物学实验、转基因动物实验，观察 miR-143/145-MDM2-p53 反馈环各节点在 VSMC生理及病理状态下表达、分布及活性改变的特征。结果：p53/MDM2 反馈环失调是主动脉夹层普遍存在的现象，并初步鉴定出TRIM25是该反馈环失调的上游调节因子。AngII能够影响小鼠主动脉VSMC中miR-143/145的表达，通过TGF-β/smad2/3通路诱导VSMC表型发生转变。p38 MAPK信号通路介导血管紧张素II诱导 miR-143/145基因簇下调进而导致主动脉夹层的形成。组织蛋白酶S参与夹层大血管重构的部分机制是通过调节PI3K/AKT 信号通路介导的p53以及p21 来影响下游凋亡激酶及凋亡抑制物的活性。在氧化应激条件下，核糖体相关蛋白BOP-1通过调控p53-MDM2反馈环的功能对于维持VSMC的正常状态具有极其重要的作用。在AMD中STIM1下调及钙库操纵的钙内流减弱介导了VSMC收缩功能的损伤。缺铁可以通过线粒体损伤，导致VSMCs表型转化，从而导致AMD。结论：miR-143/145-MDM2-p53 反馈环失衡可以通过介导VSMC发生氧化应激、代谢紊乱、表型转换、细胞凋亡等途径导致AMD的发生。