Background and Aim Adiponectin(APN) is a potent cardioprotective molecule.The present study aims to investigate the under-lying mechanism(s) for its cardioprotective effect.Methods Primary cardiomyocytes were isolated from neonatal rats and an invitro model of hypoxia-reoxygenation(H/R) was established.The cardiomyocytes were randomly divided into six groups: salinegroup(control),dithiothreitol(DTT) group(5 mmol/L DTTfor 2 h),H/R group,H/R +APN group(incubation with 30 mg/LAPN,followed by H/R),H/R +APN +SB203580(SB) group(treatment with 30 mg/L APN and 5μmol/L SB,followed by H/R),and H/R +SB group(exposure to 5μmol/L SB and then H/R).Cell death was detected by measuring lactate dehydrogenase(LDH) release.The expression levels of hypoxia-inducible factor-1alpha(HIF-1α) and endoplasmic reticulum(ER) stress-relatedgenes including GRP78,caspase-12,C/EBP homologus protein(CHOP),and p38 mitogen-activated protein kinase(MAPK) wereexamined.Results Cardiomyocytes exposed to H/R showed a significant increase in LDH leakage and HIF-1αprotein levelscompared with the control cells(p<0.05).The H/R-provoked cell death was profoundly attenuated by the pretreatment with APNalone,SB alone,or both,which was coupled with decreased expression of GRP78,caspase-12,CHOP,and p38 MAPK.Conclu-sions These results provide new insights into the mechanism of APN-mediated cardioprotection,which may be partially due to inhibi-tion of ER stress response.