Antolic Andrew, Richards Elaine M, Wood Charles E, Keller-Wood Maureen
Department of Pharmacodynamics, University of Florida, Gainesville, FL, United States.
Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, United States.
Front Physiol. 2019 Jul 3;10:816. doi: 10.3389/fphys.2019.00816. eCollection 2019.
treatment with glucocorticoids have been suggested to reprogram postnatal cardiovascular function and stress responsiveness. However, little is known about the effects of prenatal exposure to the natural corticosteroid, cortisol, on postnatal cardiovascular system or metabolism. We have demonstrated an increased incidence of stillbirth in sheep pregnancies in which there is mild maternal hypercortisolemia caused by infusion of 1 mg/kg/d cortisol. In order to model corticosteroid effects in the neonate, we created a second model in which cortisol was infused for 12 h per day for a daily infusion of 0.5 mg/kg/d. In this model we had previously found that neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group, and that neonatal ponderal index and kidney weight were reduced and left ventricular 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 hypercortisolemia in these 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 transcriptomic model indicates suppression of genes in pathways for fatty acid and ketone production and upregulation of genes in pathways for angiogenesis in the epicardial adipose fat (EAT). The transcriptomic model indicates that RNA related pathways are overrepresented by downregulated genes, but ubiquitin-mediated proteolysis and protein targeting to the mitochondria are overrepresented by upregulated genes in the intraventricular septum (IVS) and left ventricle (LV). In IVS the AMPK pathway and adipocytokine signaling pathways were also modeled based on overrepresentation by downregulated genes. Peroxisomal activity is modeled as increased in EAT, but decreased in LV and IVS. Our results suggest that pathways for lipids as well as cell proliferation and cardiac remodeling have altered activity postnatally after the cortisol exposure. Together, this model is consistent with the observed increase in cardiac wall thickness at necropsy and altered glucose metabolism observed , and predicts that exposure to excess maternal cortisol will cause postnatal cardiac hypertrophy and altered responses to oxidative stress.
有人提出，使用糖皮质激素可重新编程产后心血管功能和应激反应能力。然而，关于产前暴露于天然皮质类固醇皮质醇对产后心血管系统或新陈代谢的影响，人们知之甚少。我们已经证明，在绵羊妊娠中，通过输注1毫克/千克/天的皮质醇导致母体轻度高皮质醇血症时，死产的发生率会增加。为了模拟皮质类固醇对新生儿的影响，我们创建了第二个模型，即每天输注0.5毫克/千克/天的皮质醇，持续12小时。在这个模型中，我们之前发现，与对照组相比，新生儿血浆葡萄糖增加，血浆胰岛素减少，并且在2周龄的羔羊中，新生儿体重指数和肾脏重量降低，左心室壁厚度增加。在本研究中，我们使用转录组学模型来更好地理解这种母体高皮质醇血症对这些心脏的编程作用。这是一个终末分化以及心脏代谢从碳水化合物向脂质氧化转变被认为已经完成的时期。转录组学模型表明，心外膜脂肪（EAT）中脂肪酸和酮生成途径中的基因受到抑制，而血管生成途径中的基因上调。转录组学模型表明，与RNA相关的途径在下调基因中占比过高，但在室间隔（IVS）和左心室（LV）中，泛素介导的蛋白水解和蛋白质靶向线粒体在上调基因中占比过高。在IVS中，基于下调基因的占比过高，还对AMPK途径和脂肪细胞因子信号通路进行了建模。过氧化物酶体活性在EAT中被模拟为增加，但在LV和IVS中降低。我们的结果表明，在暴露于皮质醇后，脂质以及细胞增殖和心脏重塑的途径在出生后其活性发生了改变。总之，这个模型与尸检时观察到的心脏壁厚度增加以及观察到的葡萄糖代谢改变一致，并预测暴露于过量的母体皮质醇将导致产后心脏肥大以及对氧化应激的反应改变。
