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

血管紧张素-(1-7) 缺乏会改变大脑中与 ROS 和 NO 相关的信号通路

• 批准号: 9470487
• 负责人: Alexa Hendricks
• 金额: $ 4.5万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-28 至 2018-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470487
• 关键词: Adult; Adult Children; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Angiotensin II; Angiotensins; Animals; Anxiety; Area; Attenuated; Baroreflex; Basic Science; Betamethasone; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell physiology; Cerebrospinal Fluid; Chronic; Chronic Disease; Clinical; Complement; Data; Dementia; Developed Countries; Developing Countries; Disease; Dorsal; Down-Regulation; Endothelial Cells; Epidemiology; Event; Exhibits; Exposure to; Female; Fetal Development; Fetal Lung; Functional disorder; Future; General Population; Glucocorticoids; Glutamates; Goals; Heart Rate; Hippocampus (Brain); Human; Impaired cognition; Impairment; Incidence; Individual; Infant Mortality; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Intervention; Kidney; Knowledge; Lead; Learning; Leptin; Link; MAPK3 gene; Memory; Metabolic; Mitogen-Activated Protein Kinases; Mitogens; Modeling; Neurodegenerative Disorders; Neuroglia; Neurons; Nitric Oxide; Nucleus solitarius; Outcome; Oxidative Stress; Pathway interactions; Pattern; Peptides; Phase; Phosphatidylinositols; Phosphotransferases; Physiological; Play; Population; Premature Labor; Production; Public Health; Publications; Reactive Oxygen Species; Regulation; Renin-Angiotensin System; Reporting; Research; Risk; Risk Factors; Role; Sampling; Sheep; Signal Pathway; Signal Transduction; Staining method; Stains; Steroids; Supplementation; System; Techniques; Testing; Tissues; Water-Electrolyte Balance; Woman; angiotensin I (1-7); cell type; fetal; fetal programming; gamma-Aminobutyric Acid; glial activation; glycogen synthase kinase 3 beta; heart rate variability; human subject; improved; inflammatory marker; insight; interest; lung development; lung maturation; male; nervous system disorder; neuropathology; neurotransmission; new therapeutic target; post-doctoral training; prenatal exposure; pressure; prevent; protein expression; racial health disparity; receptor; receptor expression; relating to nervous system; response; routine therapy; sensory integration; sex; trend

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.

项目摘要 糖皮质激素（GCS）包括倍他酮（BM）是对有风险的女性进行常规治疗 早产劳动，以促进胎儿肺发育并降低婴儿死亡率。但是，胎儿类固醇 暴露可能会导致自主法规的长期影响。在胎儿的绵羊模型中 编程，暴露于BM（BMX）成人后代暴露的升高平均动脉压（MAP），精制 用于控制心率和胰岛素抵抗的压力反射灵敏度（BRS）伴随着失调 大脑，肾脏和循环肾素 - 血管紧张素系统（RAS）。 延髓和脑脊液来自第四心室，这是自主融合的主要区域，有一个变化 朝着交感神经激活剂血管紧张素II（ANG II）和通过AT1受体的作用 血管紧张素 - （1-7）[Ang-（1-7）]在男女中BRS调节的MAS受体中的有益作用。这 信号传导机制和氧化应激和/或炎症途径改变的程度 给定BMX的动物中的大脑尚未确定。我的论文已经确定了胎儿的后果 尤其是12个月大时，成人脑髓质内细胞内信号传导暴露于GC，两个 血管紧张素，胰岛素和瘦素的作用中突出的关键途径：有丝分裂激活激活激酶 途径（MAPK）和磷酸肌醇3-激酶途径（PI3K）。我的数据表明性别特异性的MAL自适应 这两种信号通路的变化（男性的磷酸化ERK1/2增加；减少 女性的磷酸化Akt和GSK-3β）在大脑的心血管中心内 ANG肽的加工不当，进而会影响氧化应激，注射和交感神经 出路。然后，我检验了以下假设：替代Ang-（1-7）通过4-5中的脑室内输注替换 一个月大的BMX绵羊，这已经证明可以防止血压升高并改善BaroreFlex 灵敏度，对信号传导的反向编程影响，氧化应激和炎症，提供了洞察力 Ang-（1-7）动作的机制。初步数据表明，在男性BMX绵羊中替换Ang-（1-7） 与给定的BMX雄性相比 ACSF。 BRS和ERK1/2的逆相关存在趋势和显着的逆相关性 MAS受体表达和血压。我未来的研究将提供有关更改的信息 信号通路及其下游效应器机制（活性氧，一氧化氮和 炎症）由BMX引起的Ang-（1-7） - Mas受体轴的下调，这可能导致 许多神经失调和疾病；确实，MAPK和PI3K途径已与 阿尔茨海默氏病的形成。我未来的兴趣是在人口中调查 RAS和心脏代谢功能在认知能力下降。具有更流行病学和公共卫生 方法我希望有助于更好地理解与衰老疾病有关的因素。