Abstract: AIM To explore the role of the PERK-ATF4-CHOP pathway in melatonin attenuated cardiomyocyte hypertrophy induced by angiotensin II (AngII). METHODS Cells were divided randomly into three groups: the blank control group, the AngII-stimulated group, the melatonin group. Lactate dehydrogenase (LDH) release was used to test cell viability. TUNEL staining was used to detect the apoptosis. Western blot method was used to detect the expression of PERK, ATF4 and CHOP. Real time-PCR was used to detect gene expression of ANP, BNP and β-MHC. Immunostaining was used to observe the cell morphology by α-actinin. RESULTS Compared with those in the control group, AngII pretreatment significantly augmented the expression of ANP, BNP and β-MHC, up-regulated LDH activity and apoptosis (P<0.05), and increased cell cross-sectional area of myocardial cells (P<0.05). Melatonin treatment resulted in reduction of expression of ANP, BNP and β-MHC (P<0.05), down-regulation of cardiomyocyte LDH activity and apoptosis (P<0.05), and the inhibition of cardiomyocyte hypertrophy (P<0.05). Moreover, Western blot analysis revealed that AngII exhibited a marked augmentation of the protein of ERK, ATF4 and CHOP (P<0.05), whereas melatonin suppressed the activation of ERK, ATF4 and CHOP stimulated by AngII (P<0.05). CONCLUSION SThe present study suggests that melatonin attenuates cardiomyocyte hypertrophy induced by AngII through the endoplasmic reticulum stress PERK-ATF4-CHOP signaling pathway. These results contribute to providing new therapeutic targets for future clinical treatment with melatonin.