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Effect of ~ 25 days cortisol treatment on late gestation fetal left ventricle

ABSTRACT: We have previously shown in sheep that 10 days of modest chronic increase in maternal cortisol result in fetal heart enlargement and Purkinje cell apoptosis. In subsequent studies in which we extended the duration of cortisol infusion (1mg/kg/d) to term, we found a dramatic incidence of stillbirth in the pregnancies with chronically increased cortisol and associated maternal hyperglycemia. In previous studies of the intraventricular septum from these fetuses we found significantly differentially regulated genes in the term fetuses (ie after ~25 days of cortisol) in pathways consistent with altered metabolism in the heart, particularly in mitochondria, associated with responses to hypoxia and to nutrient. Analysis of mitochondrial number by quantitative real-time PCR confirmed a significant decrease. We extended this investigation to the left ventricular free wall of these fetuses.le. Fewer genes were differentially regulated in left ventricle in the near term fetuses. In the LV of this cohort of fetuses, the nonredundant KEGG pathways represented by the DEG were insulin resistance and adipocytokine signaling pathway. GSEA analysis of the DEG in LV identified metabolic pathways as the nonredundant pathway altered. Comparison of the change in gene expression in biceps to that in cardiac intraventricular septum and left ventricle showed few common genes with little overlap in specific metabolic or signaling pathways, despite effects on mitochondria and metabolism in both heart and biceps. Our results suggest that glucocorticoid exposure affects nuclear genes important to mitochondrial activity and reactive oxygen in both cardiac and skeletal muscle tissues in a tissue specific manner.

ORGANISM(S): Ovis aries

PROVIDER: GSE136315 | GEO | 2019/11/01

REPOSITORIES: GEO

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Project description: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.

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Effect of ~ 25 days cortisol treatment on late gestation fetal left ventricle

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