Aim To study the cardioprotection of cardiotrophin-1(CT-1) and investigate the signaling pathways involved in the protective effect of CT-1.Methods Cardiomyocytes from the hearts of 1-3-day-old neonatal rats were prepared by a modified method.Five groups were included in the study:control group,hypoxia/reoxygenation group,hypoxia/ reoxygenation+CT-1 group,hypoxia/reoxygenation+CT-1+PD98059(ERK inhibitor) group,and hypoxia/reoxygenation+CT-1+DMSO group.The concentration of CT-1 was 10 μg/L.Myocytes survival rate was evaluated by MTS method,apoptosis,mitochondrial permeability transition pore(Δψm) and reactive oxygen species(ROS) were detected by flow cytometer.The expression of Bad mRNA was measured by RT-PCR,phosphorated ERK1/ERK2 protein level was measured by Western blot.Results Cardiomyocyte apoptosis and ROS(19.4%±2.3% vs 2.2%±0.2% and 14.28±1.42 vs 3.54±0.46;P<0.05) and the expression of Bad mRNA increased markedly after hypoxia/reoxygenation,but cardiomyocyte survival rate and the level of Δψm decreased significantly.Phosphorated ERK1/2 protein level decreased significantly.With CT-1 intervention,cardiomyocyte survival rate increased markedly,apoptosis and ROS reduced significantly.The level of Δψm increased.Expression of Bad mRNA downregulated and phosphorated ERK1/2 protein level increased.The effects of CT-1 could be inhibited by PD98059,which confirmed that PD98059 specifically involved blocking the protective effect of CT-1.Conclusions CT-1 can protect cardiac cells against hypoxia/reoxygenationinjury,these effects are dependent upon its ability to activate the extracellular signal regulated kinase ERK1/2 pathway.