乙醛脱氢酶2对主动脉夹层的影响及其机制研究

Aortic dissection (AD) is an emergency and severe disease with persistent high fatality for many years. Medical field has been continuously focusing on its pathogenesis and early screening of high-risk individuals to decrease the fatality. Aldehyde dehydrogenase 2 (ALDH2) is an enzyme which has been recently confirmed to be closely associated with cardiovascular disease. Currently, our team has found that ALDH2 regulated atherosclerotic plaque stability through change of inflammation, collagen content and macrophages in atherosclerotic plaques. Furthermore, our case-control study also showed the relation between ALDH2 Glu504Lys polymorphism and AD. Up to now, no similar research has been reported in the world. Therefore, we will investigate the effects and underlying vital mechanisms of ALDH2 on AD with in vivo and in vitro experiments with knockout rats in this research. Because of high mutation ratio of ALDH2 gene in Chinese Han nationality (30%-50%), our research will have an important clinical value and social significance by improving early warning, ameliorating early and target intervention and reducing the fatality in AD susceptible population, especially in Chinese.

主动脉夹层（AD）是一种致死率极高的心血管急危重症,多年来病死率居高不下。导致该现状的关键之一在于，早期预警、干预手段的匮乏，因此，充分阐明AD发病机制和寻找筛选高危个体的手段一直是医学界研究的热点。近年研究发现，乙醛脱氢酶2（ALDH2）与心血管疾病密切相关，本课题组在该领域研究十余年（发表10余篇SCI论文，获教育部一等奖1项）。近期我们发现，ALDH2通过调控炎症影响粥样硬化斑块胶原、平滑肌及巨噬细胞含量，进而影响其稳定性，在该新发现基础上，进一步的病例对照研究也证实ALDH2基因Glu504Lys多态与AD密切相关。我们拟通过敲基因动物和细胞实验深入探讨ALDH2对AD的影响程度及其关键机制，检索文献，迄今尚未见该方面研究。基于中国汉族ALDH2基因30%-50%的高突变率（可导致酶活性显著降低），本研究必将对促进AD，尤其是我国AD的早期筛选、靶点干预，降低致死率，具有重要意义。

主动脉夹层（AD）是一种致死率极高的心血管急危重症，多年来病死率居高不下。导致该现状的关键之一在于，早期预警、干预手段的匮乏，因此，充分阐明AD发病机制和寻找筛选高危个体的手段一直是医学界研究的热点。主动脉夹层主要有中膜平滑肌细胞的功能障碍、炎症细胞的浸润、细胞外基质的降解等病理特点。血管平滑肌细胞表型转化是功能障碍的原因之一，并且已被证实是主动脉夹层的关键起始步骤。我们利用双敲小鼠(ApoE-/-ALDH2-/-小鼠)以及人和小鼠原代平滑肌细胞，明确了乙醛脱氢酶2（ALDH2）通过影响血管平滑肌细胞表型转化在主动脉夹层发生发展中的作用。在此基础上，我们通过对ALDH2基因敲除型小鼠以及对应野生型小鼠的血管进行microRNA筛选以及生信分析，发现了两个microRNA和调控平滑肌细胞表型转化某关键分子mRNA有结合位点。通过系列细胞和动物实验明确了ALDH2影响主动脉夹层的分子机制，基于中国汉族ALDH2基因高突变率（可导致酶活性显著降低），本研究必将对促进AD，尤其是我国AD的早期筛选、靶点干预、降低病死率，具有重要意义。