动脉粥样硬化斑块易发生在形成震荡剪切力的动脉部位。我们发现在动脉粥样硬化易感部位，内皮NADPH氧化酶4(Nox4)的表达明显降低而可溶性环氧化物水解酶(sEH)的表达明显升高。Nox4是内皮NADPH氧化酶最主要的组分，它与动脉粥样硬化的关系及调控机制目前还不清楚。我们发现内皮Nox4负向调控sEH的表达和动脉粥样硬化的进程。我们推测在动脉粥样硬化易感部位，内皮Nox4可能作为震荡剪切力的感应器上调了sEH的表达，导致内皮功能异常和动脉粥样硬化的发生。利用培养的内皮细胞和内皮特异性Nox4转基因小鼠，本课题通过探讨：(1)剪切力调控Nox4的作用机制；(2)Nox4调控sEH的作用机制；(3)Nox4是否通过对sEH的调控来影响内皮功能和动脉粥样硬化；(4)其他参与内皮Nox4对动脉粥样硬化调控的基因，来阐明内皮Nox4与动脉粥样硬化的关系及调控机制，为改善动脉粥样硬化提供干预靶点。

In atherosclerosis, plaques preferentially develop in arterial regions of oscillatory shear stress. In atherosclerosis-prone regions, we found that endothelial Nox4-based NADPH oxidase was significantly down-regulated while soluble epoxide hydrolase 2 was significantly up-regulated. Nox4 as the major component of NADPH oxidases in endothelium, its relationship with atherosclerosis and the potential mechanisms involved are not clear at all. We found that endothelial Nox4 inversely regulated the expression of soluble epoxide hydrolase 2 and the progress of atherosclerosis. We hypothesized that in atherosclerosis-prone regions, endothelial Nox4 might act as an oscillatory shear stress sensor to up-regulate soluble epoxide hydrolase 2, which leads to endothelial dysfunction and the development of atherosclerosis. In this study, by using cultured endothelial cells and endothelial specific Nox4 transgenic mouse lines, we will explore: (1) the mechanisms of shear stress on regulation of Nox4 expression; (2) the mechanisms of Nox4 on regulation of the expression of soluble epoxide hydrolase 2; (3) whether the impact of Nox4 on endothelial functions and the progress of atherosclerosis is mediated by its regulation on soluble epoxide hydrolase 2; (4) other genes regulated by Nox4 involved in atherosclerosis, to address the relationship between endothelial Nox4 and atherosclerosis and the potential mechanisms involved, which will inform the development of therapeutic interventions to improve atherosclerosis.