Objective: Apelin is the endogenous peptide of the G protein coupled receptor,APJ.Monocytes (MCs) and human umbilical vein endothelial cells (HUVECs) express both apelin and APJ,which are play important roles in the physiological processes of atherosclerosis.Our previous research has characterized that apelin-13 enhanced monocytes and HUVECs adhesion.However,litter is known about the mechanism.Thus,the aim of this study is to explore the mechanism responsible for monocytes-HUVECs adhesion enhanced by apelin-13.Methods: Used western blot to detect the expression of NOX4,Beclin1,LC3Ⅱ/Ⅰ,ICAM-1,β-Tublin and β-Actin.Used DCFH-DA to label ROS,the generation of ROS was detected by fluorescence microscopy or multifunctional microplate.Used adenovirus,which expressed mRFP-GFP-LC3 fusion protein,to infect human umbilical vein endothelial cells,marking and tracing of intracellular LC3,then reflected intracellular autophagy flow by fluorescence microscopy.Used Calcein AM to label THP-1 cells,fluorescent microscope and multifunctional microplate reader detected the cells adhesion.Used siRNA to silence beclin-1 and LC3 in human umbilical vein endothelial cells and observed cell adhesion.Results: Firstly,apelin-13 promoted reactive oxygen species (ROS)generation in HUVECs,which was inhibited by DPI,a NOX inhibitor,and LY294002,a PI3K inhibitor.Secondly,apelin-13 promoted NOX4 generation in HUVECs,both of the ROS and NOX4 generation were blocked by Class Ⅲ PI3K inhibitor 3-MA.Besides,apelin-13 increased autophagy protein beclin1 and LC3-Ⅱ/Ⅰ expression in HUVECs,which was blocked by NAC,a ROS scavenger,catalase,a H2O2 enzymes scavenger and DPI.In addition,the formation of autophagy flux induced by apelin-13 cant be inhibited by hydroxychloroquine (HCQ),an autophagosome degradation inhibitor,however,was inhibited by NAC and catalase.Moreover,MCs-HUVECs adhesion induced by apelin-13 was blocked by NAC,catalase,DPI.Furthermore,down-regulation of beclinl and LC3 used siRNA blocked MCs-HUVECs adhesion.Likewise,rapamycin,an autophagy inducer enhanced MCs-HUVECs adhesion and upregulated ICAM-1 expression,which also blocked by NAC,Catalase,DPI and 3-MA.Finally,Apelin-13 led atherosclerotic plaque to appear in ApoE-/-mouse model coronary artery.The levlel of NOX4 and LC3 Ⅱ/Ⅰ increased in atherosclerotie plaque area.Conclusion: Our results demonstrated apelin-13 induced MCs-HUVECs adhesion by Class Ⅲ PI3K-NOX4-ROS-autophagy pathway.Our discovery further provided a theoretical basis for atheroselerosis treatment.