Previous studies in our laboratory have suggested that the increase in stillbirth in pregnancies complicated by chronic maternal stress or hypercortisolemia is associated with cardiac dysfunction in late stages of labor and delivery. Transcriptomics analysis of the overly represented differentially expressed genes in the fetal heart of hypercortisolemic ewes indicated involvement of mitochondrial function. Sodium dichloroacetate (DCA) has been used to improve mitochondrial function in several disease states. We hypothesized that administration of DCA to laboring ewes would improve both cardiac mitochondrial activity and cardiac function in their fetuses. Four groups of ewes and their fetuses were studied: control, cortisol-infused (1 g/kg/day from 115 to term; CORT), DCA-treated (over 24 h), and DCA + CORT-treated; oxytocin was delivered starting 48 h before the DCA treatment. DCA significantly decreased cardiac lactate, alanine, and glucose/glucose-6-phosphate and increased acetylcarnitine/isobutyryl-carnitine. DCA increased mitochondrial activity, increasing oxidative phosphorylation (PCI, PCI + II) per tissue weight or per unit of citrate synthase. DCA also decreased the duration of the QRS, attenuating the prolongation of the QRS observed in CORT fetuses. The effect to reduce QRS duration with DCA treatment correlated with increased glycerophosphocholine and serine and decreased phosphorylcholine after DCA treatment. There were negative correlations of acetylcarnitine/isobutyryl-carnitine to both heart rate (HR) and mean arterial pressure (MAP). These results suggest that improvements in mitochondrial respiration with DCA produced changes in the cardiac lipid metabolism that favor improved conduction in the heart. DCA may therefore be an effective treatment of fetal cardiac metabolic disturbances in labor that can contribute to impairments of fetal cardiac conduction.

Maternal stress in pregnancy is thought to be a contributing factor in adverse pregnancy outcomes, including stillbirth and prematurity. Previous studies in our laboratory have shown that chronic elevation in maternal cortisol concentration in ewes (by maternal infusion of 1 mg/kg/day) during the late gestation increased the incidence of stillbirth and altered fetal heart rate and blood pressure at birth. We designed the current study to test the effect of chronically elevated maternal cortisol on fetal cardiac adaption from in utero life to ex utero life. The combined risk of stillbirth or prematurity was significantly greater in the pregnancies with maternal hypercortisolemia; in this cohort, 40% of the lambs of cortisol-infused ewes died in utero or at birth compared with 25% of lambs of control ewes, and 24% of lambs of cortisol-infused ewes were born preterm, whereas no lamb was born preterm in the control group. Compared with control lambs, the lambs of cortisol-infused ewes born at full term exhibited a significant increase in mean aortic pressure just before birth and a significant decrease in mean aortic pressure that was evident during the first 9 h after birth. The QT interval was decreased before birth and increased immediately after birth in the newborns of cortisol-treated ewes compared with control lambs. These findings suggest that excess in utero corticosteroid exposure adversely affects fetal cardiac adaptation to extrauterine life and that chronic maternal stress or hypersecretion of corticosteroids may contribute to adverse obstetric outcomes.

Ovine models of pregnancy have been used extensively to study maternal–fetal interactions and have provided considerable insight into nutrient transfer to the fetus. Ovine models have also been utilized to study congenital heart diseases. In this work, we demonstrate a comprehensive assessment of heart function and metabolism using a perinatal model of heart function with the addition of a [U-13C]glucose as tracer to study central energy metabolism. Using nuclear magnetic resonance spectroscopy, and metabolic modelling, we estimate myocardial citric acid cycle turnover (normalized for oxygen consumption), substrate selection, and anaplerotic fluxes. This methodology can be applied to studying acute and chronic effects of hormonal signaling in future studies.

We have identified effects of elevated maternal cortisol (induced by maternal infusion 1 mg·kg-1·day-1) on fetal cardiac maturation and function using an ovine model. Whereas short-term exposure (115-130-day gestation) increased myocyte proliferation and Purkinje fiber apoptosis, infusions until birth caused bradycardia with increased incidence of arrhythmias at birth and increased perinatal death, despite normal fetal cortisol concentrations from 130 days to birth. Statistical modeling of the transcriptomic changes in hearts at 130 and 140 days suggested that maternal cortisol excess disrupts cardiac metabolism. In the current study, we modeled pathways in the left ventricle (LV) and interventricular septum (IVS) of newborn lambs after maternal cortisol infusion from 115 days to birth. In both LV and IVS the transcriptomic model indicated over-representation of cell cycle genes and suggested disruption of cell cycle progression. Pathways in the LV involved in cardiac architecture, including SMAD and bone morphogenetic protein ( BMP) were altered, and collagen deposition was increased. Pathways in IVS related to metabolism, calcium signaling, and the actin cytoskeleton were altered. Comparison of the effects of maternal cortisol excess to the effects of normal maturation from day 140 to birth revealed that only 20% of the genes changed in the LV were consistent with normal maturation, indicating that chronic elevation of maternal cortisol alters normal maturation of the fetal myocardium. These effects of maternal cortisol on the cardiac transcriptome, which may be secondary to metabolic effects, are consistent with cardiac remodeling and likely contribute to the adverse impact of maternal stress on perinatal cardiac function.

Background We have previously shown that monocyte chemotactic protein-1 (MCP-1) promotes aneurysm healing. Objective To determine the temporal cascade and durability of aneurysm healing. Methods Murine carotid aneurysms were treated with MCP-1-releasing or poly(lactic-co-glycolic) acid (PLGA)-only coils. Aneurysm healing was assessed by quantitative measurements of intraluminal tissue ingrowth on 5m sections by blinded observers. Results Aneurysm healing occurred in stages characteristic of normal wound healing. The 1st stage (day 3) was characterized by a spike in neutrophils and T cells. The 2nd stage (week 1) was characterized by an influx of macrophages and CD45+ cells significantly greater with MCP-1 than with PLGA (p<0.05). The third stage (week 2-3) was characterized by proliferation of smooth muscle cells and fibroblasts (greater with MCP-1 than with PLGA, p<0.05). The fourth stage (3-6months) was characterized by leveling off of smooth muscle cells and fibroblasts. M1 macrophages were greater at week 1, whereas M2 macrophages were greater at weeks 2 and 3 with MCP-1 than with PLGA. Interleukin 6 was present early and increased through week 2 (p<0.05 compared with PLGA) then decreased and leveled off through 6months. Tumour necrosis factor was present early and remained constant through 6months. MCP-1 and PLGA treatment had similar rates of tissue ingrowth at early time points, but MCP-1 had a significantly greater tissue ingrowth at week 3 (p<0.05), which persisted for 6months. Conclusions The sequential cascade is consistent with an inflammatory model of injury, repair, and remodeling.

Obesity confers an independent risk for carcinogenesis. In the liver, steatosis often proceeds cancer formation; however, the mechanisms by which steatosis promotes carcinogenesis is unknown. We hypothesize that steatosis alters the microenvironment to promote proliferation of tumor initiating cells (TICs) and carcinogenesis. We used several liver cancer models to address the mechanisms underlying the role of obesity in cancer and verified these findings in patient populations. Using bioinformatics analysis and verified by biochemical assays, we identified that hepatosteatosis resulting from either Pten deletion or transgenic expression of HCV core/NS5A proteins, promotes the activation of Wnt/β-catenin. We verified that high fat diet lipid accumulation is also capable of inducing Wnt/β-catenin. Caloric restriction inhibits hepatosteatosis, reduces Wnt/β-catenin activation and blocks the expansion of TICs leading to complete inhibition of tumorigenesis without affecting the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) loss regulated protein kinase B (AKT) activation. Pharmacological inhibition or loss of the Wnt/β-catenin signal represses TIC growth in vitro, and decreases the accumulation of TICs in vivo. In human liver cancers, ontology analysis of gene set enrichment analysis (GSEA)-defined Wnt signature genes indicates that Wnt signaling is significantly induced in tumor samples compared with healthy livers. Indeed, Wnt signature genes predict 90% of tumors in a cohort of 558 patient samples. Selective depletion of macrophages leads to reduction of Wnt and suppresses tumor development, suggesting infiltrating macrophages as a key source for steatosis-induced Wnt expression. These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.