肌浆网/内质网钙ATP酶2对维持内质网钙稳态至关重要。位于674位的半胱氨酸(C674)是SERCA2的主要氧化还原位点，在形成动脉粥样硬化的病理条件下，其不可逆性氧化可以抑制SERCA2的功能,推测与动脉粥样硬化的形成有关。利用SERCA2 C674S 基因敲入鼠(SKI)来模拟这个位点的失活，我们发现SKI促进动脉粥样斑块的生成，表明SERCA2 C674的失活直接参与了动脉粥样硬化的进程。在巨噬细胞上，SKI下调胰岛素受体水平，上调CHOP的表达，推测SKI对这些基因的调控参与了动脉粥样硬化的进程。利用SKI和CHOP敲除小鼠，本课题拟从巨噬细胞角度探讨C674的失活与动脉粥样硬化的关系及调控机制，为动脉粥样硬化的防治提供新的理论依据和干预靶点。

Atherosclerosis is the leading cause of death and poses an increasing threat to human health worldwide. Knowledge of the related regulation mechanism of atherosclerosis may have significance for understanding the causes of the diseases, and could be helpful for rational design of novel therapeutic and diagnostic methods. Sarco/endoplasmic reticulum calcium ATPase 2 (SERCA2) is critical to maintain calcium homeostasis in the endoplasmic reticulum (ER). Cysteine 674 (C674) is the main redox site of SERCA2, which plays a key role in regulating SERCA2 activity. Under pathological conditions, however, C674 is easily irreversibly oxidized and fails to stimulate SERCA2 activity, which suggested to be related with the pathogenesis of atherosclerosis. Using SERCA2 C674S knock-in mice (SKI) to mimic the inactivation of C674 in pathological conditions, we found that SKI significantly accelerated the formation of atherosclerotic plaque, suggesting inactivation of C674 is directly involved in the pathogenesis of atherosclerosis. Moreover, SKI decreased the level of insulin receptor in macrophage, while CHOP (C/EBP homologous protein) was up-regulated, which revealed the regulation of SKI on these genes may partially mediated the occurrence of atherosclerosis. In this project, using SKI and CHOP knockout mice, we will investigate the effect of SERCA2 C674 inactivation on atherosclerosis in macrophage, and explore the potential mechanism involved thus providing new theory and therapeutic target for clinical prevention and treatment of atherosclerosis.