Maternal obesity causes a sex-dependent increase in AT2 R expression and cardiac dysfunction in adult male offspring

Aim Maternal obesity is associated with cardiovascular disease later in life. Here we report that mater- nal obesity causes programming of increased cardiac AT2 receptor （ AT2R） expression, resulting in heightened car- diac susceptibility to ischemic injury in a sex-dependent manner. Methods Pregnant rats were divided between control and obese （high fat diet-fed during gestation） groups. Effects of obesity on cardiac function and heart sus- ceptibility to ischemia-reperfusion （I/R） injury in offspring were determined by echocardiography or langendofff. Results Maternal obesity resulted in cardiac hypertrophy in only male offspring, but had no effect on cardiac func- tion 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 fe- male offspring. However, maternal obesity had no effect on AT1R in both male and female offspring. Obesity resul- ted in decreased glucocorticoid receptors （GRs） binding to the glucocorticoid response elements （GREs） at the AT2R promoter, which was due to decreased GRs and binding affinity of GR to GREs in the heart of adult male off- spring. Inhibition of ATzR with PD 123,319 abrogated maternal obesity-induced increase in cardiac ischemic vul- nerability in male adult rats. Conclusions Maternal obesity causes programming of increased ATzR gene expres- sion in the heart by downregulation of GR, contributing to the heightened cardiac vulnerability to ischemic injury in male offspring in a sex-dependent manner.