A Transcriptomic Model of Postnatal Cardiac Effects of Prenatal Maternal Cortisol Excess In Sheep

Cortisol administration during late gestation in ewes, modeling maternal stress, resulted in transcriptomic changes suggesting altered maturation and metabolic changes to the offspring heart. Pregnant ewes were treated with 0.5 mg/kg/day cortisol from 115 days gestation to term lambs were studied over the next 2 weeks. Left ventricular free wall (LV) and intraventricular septum (IVS) were collected at 2 weeks of age (lambs of control, untreated ewes: n=8, lambs of ewes treated with 0.5 mg/kg/day: n=8). In this model we found that neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group. LV free wall thickness was increased in the 2 week old lamb. In this study, we have used transcriptomic modeling to better understand the programming effect of this maternal cortisolemia in the 2 week old hearts. This is a time when both terminal differentiation and a shift in the metabolism of the heart from carbohydrates to lipid oxidation are thought to be complete. The transcriptomics indicates downregulation of RNA related pathways, but upregulation of ubiquitin-mediated proteolysis and protein targeting to the mitochondria in in the intraventricular septum (IVS) and left ventricle (LV) in lambs of cortisol-infused ewes compared to untreated control ewes. In IVS pathways the AMPK pathway and adipocytokine signaling pathways were also modeled as downregulated in lambs of cortisl-treated ewes Genes for peroxisomal activity are modeled as decreased in LV and IVS; our previous metabolomic study of the newborn hearts from the 1 mg/kg/d study indicated changes in the plasmogens and phospholipids that are peroxisomal products. Our results suggest that pathways for lipid metabolismas well as cell proliferation and cardiac remodeling have altered activity postnatally after the in utero cortisol exposure. Together, this model is consistent with the observed increase in cardiac wall thickness at necropys and altered glucose metabolism observed in vivo, and predicts that in utero exposure to excess maternal cortisol causes postnatal cardiac hypertrophy and altered responses to oxidative stress. Left ventricular free wall and intraventricular septum were collected from 2 week old lambs of cortisol treated ewes (0.5mg/kg/day administered from 2100h to 0900h daily from day 115 fo gestation until delivery) (n=8) or untreated ewes (n=8).