乙醛脱氢酶2通过代谢4-HNE抑制血管钙化的作用及机制研究

血管钙化好发于大动脉或中动脉的内膜和中膜，不仅增加血管壁僵硬程度、引起弹性下降，还可增加动脉粥样硬化斑块不稳定性，是导致血栓形成和动脉斑块破裂等的重要病理机制。然而目前尚无有效的改善血管钙化的药物及治疗措施。我们前期利用乙醛脱氢酶2（ALDH2）基因敲除小鼠构建血管钙化模型，发现ALDH2基因敲除明显加重了血管钙化的严重程度，体外实验发现4-羟基壬烯醛（4-HNE）在血管钙化过程中明显蓄积且导致血管平滑肌细胞（VSMCs）表型转化，过表达或激活ALDH2可明显减轻这一过程。基于此，我们推测ALDH2可能通过代谢血管钙化过程中蓄积的4-HNE减弱VSMCs表型转化，进而减缓血管钙化。本项目拟从动物、细胞及分子层面展开研究，明确ALDH2在血管钙化发生发展过程中的作用，揭示ALDH2调节VSMCs表型转化参与血管钙化的具体分子机制，为防治血管钙化、减少不良心血管事件发生提供理论基础和实验依据。

Vascular calcification is most likely to occur in the intima and media of the aorta or middle artery. It can not only increase the degree of vascular wall stiffness and cause decreased elasticity, but also increase the instability of atherosclerotic plaque, which is one of the important pathological mechanisms leading to thrombosis and rupture of arterial plaque. However, there are no effective drugs and other therapeutic measures to improve vascular calcification. In our previous study, aldehyde dehydrogenase 2 (ALDH2) gene knockout mice were used to construct vascular calcification model. We found that ALDH2 gene knockout increased the severity of vascular calcification significantly. In vitro, we found that 4-hydroxynonenal (4-HNE) accumulated in the process of vascular calcification and lead to phenotypic transformation of vascular smooth muscle cells (VSMCs). In addition, overexpression or activation of its metabolic enzyme ALDH2 can significantly reduce this process. The study aims to conduct research at the animal, cellular and molecular levels. To clarify the role of ALDH2 in the occurrence and development of vascular calcification and to reveal the specific molecular mechanism of ALDH2 regulating phenotypic transformation of VSMCs in vascular calcification will provide theoretical and experimental basis for prevention and treatment of vascular calcification and reduction of adverse cardiovascular events.