Abstract P2033: Western Diet Can Cause Adverse Cardiac Remodeling During Pregnancy by Inducing Foxo1 Expression

Introduction: Pregnancy induces physiological cardiac hypertrophy in healthy women. Our recent findings suggest that obesity can disturb this process and induce pathological cardiac hypertrophy during pregnancy both in human patients and Western Diet (WD) fed mice. Animal studies determined the pathological cardiac hypertrophy is concomitant with increased cardiomyocyte cross-sectional area (CSA), fetal gene activation and fibrosis, however, the underlying mechanisms remain unclear. The present study asks if FoxO1, as a transcriptional factor, may play a role in the adverse cardiac response to pregnancy in WD mice. Methods: The expression levels of FoxO1 and its downstream targeting genes were tested in Ctrl Diet (CD) and WD fed non-pregnant and postpartum animals. To further investigate the role of FoxO1 in pathological cardiac hypertrophy in WD animals during pregnancy, FoxO1 was then silenced by AAV9-shFoxO1 virus in WD mice before breeding. AAV9-scramble RNA served as control. Cardiac phenotype in AAV9 treated WD mice were characterized at post-partum day 1. Results: WD feeding led to increased gene expression levels of FoxO1 and its downstream targeting genes, such as CD36 and PDK4, compared with CD mice. While the gene expression levels of FoxO1 were not different between non-pregnant and pregnant WD mice, FoxO1 protein activation was significantly increased in WD mice after pregnancy determined by a decrease of pFoxO1/tFoxO1 ratio, compared with non-pregnant WD mice. Silencing FoxO1 inhibited the expression levels of FoxO1 and its downstream genes CD36 and PDK4. FoxO1 inhibition in WD fed animals prevented WD induced pathological hypertrophy during pregnancy, with decreased heart weight, cardiomyocyte CSA, attenuated fetal gene activation and fibrosis accumulation. FoxO1 silencing also led to less accumulation of lipid peroxidation product in the myocardium. Conclusions: FoxO1 activation in WD mice with metabolic disturbances during pregnancy can induce pathological cardiac hypertrophy observed during pregnancy.