Abstract： Objective To investigate the effect of oxidative stress-induced CaMKⅡ activation in endothelial cells on atherosclerosis and its mechanism. Methods Human umbilical vein endothelial cells (HUVECs)were cultured in vitro and divided into the control group,H2O2group,H2O2+KN93 group,and H2O2+KN92 group. The ROS level,cell viability,migration ability,and adhesion ability were determined, and the function of endothelial cells was assessed. RT-PCR was used to determine the expression levels of CaMKⅡ,p-CaMKⅡ,ox-CaMKⅡ,notch-1,NF-κB-p65 and VCAM-1. Thirty 8-week-old male ApoE(-/-) mice were randomly divided into 3 groups:the high-fat diet group (n=10) received high-fat diet and intraperitoneal injection of DMSO;the high-fat diet+KN93 group (n=10) received high-fat diet and intraperitoneal injection of KN93(10 mg-1·kg-1·d-1);and the high-fat diet+KN92 group(n=10)received high-fat diet and intraperitoneal injection of KN92(10 mg-1·kg-1·d-1). The body weight and blood lipid level in each group were recorded. The oil Red O staining of the aorta was performed. The aortic root plaque area and aortic lipid deposition were compared between the groups. Results Compared with the H2O2+KN92 group and H2O2group,the endothelial cell viability,migration ability,and adhesion ability in the H2O2+KN93 group were all improved(P<0.05). The findings of RT-qRCR showed that the mRNA levels of notch-1 and VCAM-1 were down-regulated in the H2O2+KN93 group(P<0.05). The findings of Western blotting showed that KN93 treatment significantly decreased the protein expression levels of ox-CaMKⅡ,p-CaMKⅡ,notch-1,NF-κB-p65 and VCAM-1(P<0.05). The inhibition of notch-1 by DAPT did not affect the protein expression of CaMKⅡ,ox-CaMKⅡ,and p-CaMKⅡ. The aortic root plaque area and aortic lipid deposition in the KN93-treated ApoE-/-mice were significantly decreased compared with those in the control group and KN92 group[(25.15±1.04)% vs(41.60±1.05)% vs(41.83±1.17)%;12.70±0.89% vs(25.28± 1.77)% vs(25.57 ± 0.78)%],respectively. There were no statistically significant differences in the body weight and blood lipid levels between the groups (P>0.05). Conclusion KN93 may ameliorate the endothelial dysfunction through the CaMKⅡ/notch-1/NF-κB-p65/VCAM-1 pathway,and thereby delay the occurrence and development of atherosclerosis.