SAH水解酶下调促进动脉粥样硬化钙化形成的作用机制研究

S-腺苷同型半胱氨酸（SAH）是心血管疾病一个新的危险因素。我们前期研究发现下调SAH水解酶升高血浆SAH水平，促进动脉粥样硬化（AS）形成与发展。但是SAH水解酶下调对AS钙化的影响及机制仍不清楚。预实验发现SAH水解酶在冠心病患者钙化血管组织中低表达与钙化严重程度呈负相关。下调SAH水解酶促进平滑肌细胞（VSMC）成骨样转化。在机制的探索中，转录组测序发现lncRNA H19在SAH水解酶基因敲除小鼠中高表达，并且在钙化血管组织中高表达。据此，我们提出科学假说：SAH水解酶下调是否通过激活H19诱导 VSMC表型转化促进AS钙化形成。本项目拟探讨SAH水解酶下调对AS钙化形成的影响，探讨其机制是否通过调控H19/Notch1/Runx2信号通路调控VSMC表型转化，阐明SAH水解酶与H19互相调控的分子机制。本研究为证实SAH水解酶在AS钙化中的作用提供科学依据，为AS防治提供新思路。

S-adenosylhomocysteine (SAH) is a new risk factor of cardiovascular disease. Our previous studies found that SAH hydrolase downregulation increased plasma SAH level, and promoted the formation and development of atherosclerosis (AS). However, the effect and mechanism of SAH hydrolase downregulation on AS calcification is still unclear. In our pre-experiments, we found that the expression of SAH hydrolase was decreased in the calcified vascular specimens from patients with coronary artery disease and inversely associated with severity of coronary atherosclerotic calcification. SAH hydrolase downregulation promoted osteogenic transformation of smooth muscle cells. In exploration of the underlying mechanism, we found that the expression of lncRNA H19 was increased in the SAH hydrolase knockout mice by RNA sequencing and was increased in calcified vascular tissues. Accordingly, we propose a scientific hypothesis: whether down-regulation of SAH hydrolase promotes AS calcification by activating H19 induced VSMC phenotype transformation. In the present study, we will further determine effect of SAH hydrolase downregulation on AS calcification, and explore whether the mechanism is involved in phenotype transformation of smooth muscle cells by regulating the H19/Notch1/Runx2 signaling pathway, and further elucidate the detail molecular mechanism of the interaction between SAH hydrolase and H19 gene. This study will provide scientific basis for confirming the relationship between SAH hydrolase and AS calcification, and provide new ideas for prevention and treatment of AS.