Brain MAP Kinases - Substrate for Sympathetic Excitation in Heart Failure

脑 MAP 激酶 - 心力衰竭交感神经兴奋的底物

• 批准号: 8589602
• 负责人: Robert B Felder
• 金额: $ 37万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589602
• 关键词: Acute; Age; Aldosterone; Angiotensin II; Animals; Astrocytes; Automobile Driving; Brain; Brain region; Cardiovascular system; Cell Nucleus; Cells; Characteristics; Chronic; Complex; Development; Disease; Event; Experimental Models; Generations; Goals; Heart failure; Hospitalization; Hypothalamic structure; Individual; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-1 beta; Ischemia; Knowledge; Lead; Learning; Mediating; Mediator of activation protein; Microglia; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; NADP; Nerve; Neuraxis; Neurons; Oxidases; Oxidation-Reduction; Pathway interactions; Phenotype; Population; Process; Production; Rattus; Reactive Oxygen Species; Regulation; Renin-Angiotensin System; Role; Signal Pathway; Signal Transduction; Source; Superoxides; Sympathetic Nervous System; Syndrome; System; Systolic heart failure; TNF gene; Techniques; Therapeutic Intervention; Tumor Necrosis Factor-alpha; United States; Up-Regulation; adverse outcome; base; brain regulatory center; cell type; cytokine; human MAPK14 protein; human old age (65+); hypertensive heart disease; macrophage; mortality; neurochemistry; novel; novel strategies; paraventricular nucleus; receptor; response; statistics; stress-activated protein kinase 1; treatment strategy

Heart failure is the most common reason for hospitalization in the United States among those older than 65 years, and this statistic is expected to grow as the population ages. Overactivity of the sympathetic nervous system (SNS) is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. Recent studies suggest that altered neurochemical mechanisms in the brain contribute to the augmented SNS activity in heart failure. Several excitatory substances appear in the brain in excess quantities in heart failure. These include angiotensin II (ANG II), aldosterone (ALDO) and the pro-inflammatory cytokines (PIC). All three act to increase the production of reactive oxygen species in the brain, but beyond that it is not at all clear how they activate the SNS. We recently found that blocking one of the three major components of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade in the brain substantially reduced SNS activity in rats with heart failure. These MAPKs are sensitive to the presence of reactive oxygen species, respond to ANG II, ALDO and PIC, and, when activated, lead to the production of more excitatory neurochemical substances that may contribute to persistent activation of the SNS, which is typical of heart failure. The overall goal of this project is to determine to what extent the three major MAPK signaling pathways contribute to the excitatory neurochemical milieu in a key cardiovascular regulatory center of the brain, the paraventricular nucleus of hypothalamus (PVN), that drives SNS activity in heart failure. In rats with systolic heart failure and in normal rats treated with ANG II, ALDO and PIC to induce MAPK activity, we will determine: 1) the effects of the three major MAPK signaling pathways on the expression of excitatory mediators in the PVN; 2) the effects of MAPK signaling in the PVN on SNS activity; 3) the phenotypes of the cells in PVN - neurons, microglia, astrocytes, and perivascular macrophages - that express MAPK signaling, and their influences on the production of excitatory mediators and sympathetic excitation. A combination of molecular, immunohistochemical, and electrophysiological techniques will be used to elucidate the mechanisms by which brain MAPK signaling influences SNS activity. We hope these studies will identify novel targets for therapeutic intervention in systolic heart failure.

心力衰竭是美国最常见的住院原因 65 岁以上的人，而且这一统计数据预计会随着人口老龄化而增长。 交感神经系统（SNS）过度活跃是心脏的主要表现 失败综合症，也是发病率和死亡率的有力预测因子。最近的研究表明 大脑中神经化学机制的改变有助于增强 SNS 活动 心脏衰竭。大脑中出现的几种兴奋物质在心脏中含量过量 失败。这些包括血管紧张素 II (ANG II)、醛固酮 (ALDO) 和促炎物质 细胞因子（PIC）。这三种物质都能增加大脑中活性氧的产生， 但除此之外，还不清楚他们如何激活社交网络服务。我们最近发现阻塞 细胞内丝裂原激活蛋白激酶 (MAPK) 的三个主要成分之一 心力衰竭大鼠大脑中的信号级联反应显着降低了 SNS 活性。这些 MAPK 对活性氧的存在敏感，对 ANG II、ALDO 和 PIC 被激活后，会产生更多的兴奋性神经化学物质 这可能会导致 SNS 持续激活，这是心力衰竭的典型症状。这 该项目的总体目标是确定三大 MAPK 信号传导的程度 通路有助于关键心血管调节中的兴奋性神经化学环境 大脑中心，下丘脑室旁核 (PVN)，驱动 SNS 活动 在心力衰竭中。在收缩性心力衰竭大鼠和接受 ANG II、ALDO 治疗的正常大鼠中 和 PIC 诱导 MAPK 活性，我们将确定： 1) 三大 MAPK 的影响 PVN 兴奋性介质表达的信号通路； 2）影响 PVN 中 MAPK 信号对 SNS 活动的影响； 3）PVN中细胞的表型——神经元， 小胶质细胞、星形胶质细胞和血管周围巨噬细胞 - 表达 MAPK 信号传导及其 对兴奋性介质和交感神经兴奋的产生的影响。组合 分子、免疫组织化学和电生理学技术将用于 阐明大脑 MAPK 信号传导影响 SNS 活动的机制。我们希望 这些研究将确定收缩性心力衰竭治疗干预的新靶点。