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Aims: Apelin is the endogenous ligand for the G protein coupled receptor APJ.It promotes vascular smooth muscle cell proliferation and monocyte adhesion to endothelial cells.In our previous research,we found that apelin-13 promotes H9c2 rat cardiomyocytes hypertrophy by PI3K-Akt-ERK1/2-p70S6K and PI3K-autophagy pathway.The objective of this study was to explore the role of apelin-13 on the regulation of ER stress and autophagy,And then to investigate the association of ER stress and autophagy with the improvement of cell diameter,cell volume after giving apelin-13.Methods and results: Fuorescence microscope analysis exhibited that apelin-13 increases the production of ROS in a dose dependent manner.Electron microscope observation reflected that apelin-13(1μmol/L) activate the endoplasmic reticulum stress.Western Blot results show that apelin-13 promotes the expression of NOX4,Bip and CHOP in dose and time dependent manners.APJ shRNA,NOX4 inhibitor dibenziodolium chloride (DPI) block the increase of Bip,CHOP induced by apelin-13(1μmol/L).Apelin-13 promotes the expression of LC3-Ⅱ/Ⅰ,beclin 1and reduce the expression of p62 in dose and time dependent manners.APJ shRNA,NOX4 inhibitor DPI,endoplasmic reticulum stress inhibitor Salubrinal(10μmol/L),Bip siRNA and CHOP siRNA all can attenuate the overexpression of LC3-Ⅱ/Ⅰ,beclin 1 and cripple the decrease of p62 induced by apelin-13(1μmol/L);Scepter TM Handheld Automated Cell Counter data explain that endoplasmic reticulum stress inhibitor Salubrinal(10μmol/L),Bip siRNA,CHOP siRNA or autophagy inhibitor 3MA(5mmol/L)all weaken the increase of cell diameter,volume and intracellular protein content induced by apelin-13(2μmol/L);Endoplasmic reticulum stress revulsant Tunicamycin(1mg/L) enhanced the increase of cell diameter,volume and intracellular protein content induced by apelin-13(2μmol/L).Conclusion: These findings show that ER stress-autophagy involved in the H9c2 rat cardiomyocytes hypertrophy induced by apelin-13.