Deficiency in Angiotensin-(1-7) Alters Signaling Pathways Linked to ROS and NO in the Brain

项目摘要 糖皮质激素（GC），包括倍他米松（BM）是对有以下风险的女性的常规治疗： 早期早产有利于胎儿肺部发育，降低婴儿死亡率。然而，胎儿类固醇 暴露可能导致对自主调节的负面长期后果。在绵羊胎儿模型中， 编程，BM暴露（BMX）的成年后代表现出平均动脉压（MAP）升高， 压力反射敏感性（BRS），用于控制心率和胰岛素抵抗，伴随着 脑、肾和循环中的肾素-血管紧张素系统（RAS）。 第四脑室是自主神经整合的主要区域， 血管紧张素II（Ang II）和通过AT 1受体对抗血管紧张素II的作用。 血管紧张素-（1-7）[Ang-（1-7）]对两种性别中BRS调节的Mas受体的有益作用。的 信号传导机制和氧化应激和/或炎性途径的改变程度 BMX对动物大脑的影响还有待证实。我的论文已经建立了胎儿 暴露于GC对12个月大的成年脑髓质内细胞内信号传导的影响，特别是两个 在血管紧张素、胰岛素和瘦素的作用中起重要作用的关键途径：丝裂原活化激酶 磷酸肌醇3-激酶途径（PI 3 K）。我的数据显示性别特异性适应不良 这两种信号通路的变化（雄性中磷酸化ERK 1/2增加; 磷酸化Akt和GSK-3β）在大脑心血管中心内的表达伴随着 血管紧张素肽的不当加工，这反过来又可能影响氧化应激，炎症和交感神经系统。 外流然后，我验证了通过侧脑室输注替代Ang-（1-7）在4-5岁儿童中的作用的假设。 一个月大的小轮车羊，已经证明，以防止血压上升，提高压力感受器反射 敏感性，反向编程对信号传导，氧化应激和炎症的影响，提供了对 Ang-（1-7）作用的机制。初步数据显示，在雄性BMX绵羊中， 与BMX男性相比，这个早期年龄显着降低了ERK 1/2的磷酸化蛋白表达 aCSF BRS和ERK 1/2呈负相关趋势， Mas受体表达和血压的关系。我未来的研究将提供有关改变的信息， 信号通路及其下游效应机制（活性氧、一氧化氮和 BMX诱导的Ang-（1-7）-Mas受体轴下调可能导致炎症， 一系列神经失调和疾病;事实上，MAPK和PI 3 K通路与 阿尔茨海默病斑块形成。我未来的兴趣是研究人类中 RAS和心血管代谢功能对认知功能下降的影响随着流行病学和公共卫生 我希望能有助于更好地了解与衰老疾病相关的因素。

Project Summary Glucocorticoids (GCs) including betamethasone (BM) are routine therapy administered to women at risk of early preterm labor to facilitate fetal lung development and reduce infant mortality rates. However, fetal steroid exposure may lead to negative long term consequences for autonomic regulation. In a sheep model of fetal programming, BM-exposed (BMX) adult offspring exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for control of heart rate and insulin resistance accompanied by dysregulation of the brain, renal and circulating renin-angiotensin system (RAS).In the brain solitary tract nucleus of the dorsal medulla and cerebrospinal fluid from 4th ventricle, a major area of autonomic integration, there is a shift towards the sympathetic activator angiotensin II (Ang II) and actions through the AT1 receptor that oppose the beneficial actions of angiotensin-(1-7) [Ang-(1-7)] at the Mas receptor for BRS regulation in both sexes. The signaling mechanisms and extent of alterations in oxidative stress and/or inflammatory pathway within the brain in animals given BMX has yet to be established. My dissertation has established consequences of fetal exposure to GCs on intracellular signaling within the adult brain medulla at 12 months of age in particular, two key pathways that are prominent in the actions of angiotensins, insulin and leptin: mitogen activated kinase pathway (MAPK) and phosphoinositide 3-kinase pathway (PI3K). My data shows that sex-specific mal-adaptive changes in these two signaling pathways (increased phosphorylated ERK1/2 in males; decreased phosphorylated Akt and GSK-3β in females) within cardiovascular centers of the brain accompanies the improper processing of Ang peptides, which in turn may impact oxidative stress, inflammation and sympathetic outflow. I then tested the hypothesis that replacement of Ang-(1-7) via intracerebroventricular infusion in 4-5 month old BMX sheep, that already shown to prevent the increase in blood pressure and improve baroreflex sensitivity, reverse programming effects on signaling, oxidative stress and inflammation, providing insight into mechanisms of Ang-(1-7) actions. Preliminary data shows that replacement of Ang-(1-7) in male BMX sheep at this early age significantly lowers phosphorylated protein expression of ERK1/2 compared to BMX males given aCSF. There is a trend for an inverse correlation of the BRS and ERK1/2 and a significant inverse correlation of Mas receptor expression and blood pressure. My future studies will provide information on alterations in signaling pathways and their downstream effector mechanisms (reactive oxygen species, nitric oxide and inflammation) resulting from BMX-induced down-regulation of the Ang-(1-7)-Mas receptor axis that may lead to a host of neural dysregulation and disease; indeed, the MAPK and PI3K pathway has been implicated in Alzheimer's disease plaque formation. My future interest is to investigate in the human population the role of RAS and cardiometabolic function on cognitive decline. With a more epidemiological and public health approach I hope to contribute to better understanding of factors related to diseases of aging.