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Aim Maternal obesity is associated with cardiovascular disease later in life.Here we report that maternal obesity causes programming of increased cardiac AT2 receptor (AT2R) expression, resulting in heightened cardiac susceptibility to ischemic injury in a sexdependent manner.Methods Pregnant rats were divided between control and obese (high fat dietfed during gestation) groups.Effects of obesity on cardiac function and heart susceptibility to ischemiareperfusion (I/R) injury in offspring were determined by echocardiography or langendorff.Results Maternal obesity resulted in cardiac hypertrophy in only male offspring, but had no effect on cardiac function in both male and female offspring.Additionally, maternal obesity increased heart susceptibility to I/R injury in adult male, but not female offspring.mRNA and protein abundance of AT2R were increased in male, but not female offspring.However, maternal obesity had no effect on AT1R in both male and female offspring.Obesity resulted in decreased glucocorticoid receptors (GRs) binding to the glucocorticoid response elements (GREs) at the AT2 R promoter, which was due to decreased GRs and binding affinity of GR to GREs in the heart of adult male offspring.Inhibition of AT2R with PD 123,319 abrogated maternal obesityinduced increase in cardiac ischemic vulnerability in male adult rats.Conclusions Maternal obesity causes programming of increased AT2R gene expression in the heart by downregulation of GR, contributing to the heightened cardiac vulnerability to ischemic injury in male offspring in a sexdependent manner.