Effects of maternal cortisol on perinatal cardiac metabolism and function

项目摘要 皮质醇是胎儿器官成熟的调节剂，包括心脏。母体皮质醇过高或应激 似乎会增加足月死产的风险，并改变胎儿心脏的发育。在一个动物模型中 在妊娠晚期，母亲皮质醇升高，模拟轻微但慢性的压力，我们发现了一种惊人的 死产增加和胎儿心脏基因表达的变化表明葡萄糖的变化 代谢、线粒体功能和能量可获得性。数据支持这样一种假设，即存在 下调TCA循环活性及线粒体数量和功能。拟议的研究将测试 晚期胎儿皮质醇改变改变心脏代谢、功能和重塑的主要假说 妊娠，并最终导致胎儿心脏功能障碍，包括结构和功能的变化， 在分娩和分娩期间或在产后立即发生不良事件。我们将测试 用无线电电测法研究分娩过程中胎儿心脏病理生理学的进行性变化 监测胎儿主动脉压和心电图，超声分析胎儿心脏大小和功能，以及 转录学、代谢学、组织病理学和生化方法研究心脏的变化 结构和新陈代谢。我们将检验这一假设，即葡萄糖的正常途径受到干扰。 以及乳酸代谢和线粒体功能丧失，将反映在线粒体的变化上 呼吸测量，基因表达和代谢组学。我们将检验这样一种假设，即 心脏结构和功能的病理生理变化，这些变化将通过心室的变化来反映 超声心动图确定的大小和功能，以及主动脉压和心电图的变化。 我们还将使用13C葡萄糖流量和13C鉴定来测试心脏对葡萄糖利用的变化 血浆和心脏组织中的葡萄糖异构体。我们将进一步检验这一假设，即 心脏代谢和线粒体是心脏代谢和心电图改变的基础。 给予二氯乙酸酯，一种增加丙酮酸活性的小分子治疗药物 脱氢酶复合体，这是TCA循环活动所必需的。DCA将在 分娩，在我们的模型中，心电图异常变得明显的时间。DCA用于人类 线粒体疾病，包括患有乳酸中毒的儿童，以及这项研究的数据可能会 为新生儿的急救提供一种治疗方法。

Project Summary Cortisol is a regulator of maturation of fetal organs, including the heart. Maternal hypercortisolemia or stress appears to increase the risk of stillbirth at term and alter growth of the fetal heart. In an animal model with elevated maternal cortisol in late gestation, mimicking mild but chronic stress, we have found a striking increase in stillbirth and changes in gene expression in the fetal heart suggesting changes in glucose metabolism, mitochondrial function, and energy availability. The data support the hypothesis that there is downregulation of TCA cycle activity and mitochondrial number and function. The proposed studies will test the overarching hypothesis that alterations in fetal cortisol alter cardiac metabolism, function and remodeling in late gestation, and ultimately lead to fetal cardiac dysfunction, including both structural and functional changes, that result in adverse events during labor and delivery or in the immediate postnatal period. We will test for progressive changes in pathophysiology in the fetal heart during controlled labor using radiotelemetric monitoring of fetal aortic pressure and ECG, ultrasound analysis of fetal heart dimensions and function, and transcriptomic, metabolomic, histopathologic, and biochemical approaches to investigate changes in cardiac structure and metabolism. We will test the hypothesis that there is disruption of normal pathways for glucose and lactate metabolism and loss of mitochondrial function that will be reflected in changes in mitochondrial respirometry, gene expression and metabolomics. We will test the hypothesis that there will be pathophysiologic changes in cardiac structure and function that will be reflected by changes in ventricular dimensions and function identified by echocardiography, as well as alterations in aortic pressure, and in ECG. We will also test for alterations in glucose utilization by the heart using 13C glucose flux and identification of 13C glucose isoptomers in plasma and in the heart tissue. We will further test the hypothesis that changes in cardiac metabolism and mitochondria underlie changes in cardiac metabolism and ECG changes using administration of dichloroacetate, a small molecule therapeutic that increases activity of the pyruvate dehydrogenase complex, which is required for TCA cycle activity. DCA will be administered acutely during labor, the time at which the abnormalities in ECG become evident in our model. DCA is used in humans with mitochondrial diseases, including children with lactic acidosis, and the data from this study would potentially provide a therapeutic method for acute rescue of neonates.