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: 8038587
• 负责人: Robert B Felder
• 金额: $ 37.6万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038587
• 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 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

DESCRIPTION (provided by applicant): 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. Over activity 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. PUBLIC HEALTH RELEVANCE: This project examines the role of a critical intracellular signaling mechanism, the mitogen-activated protein kinases, in the upregulation of excitatory mediators (angiotensin II, aldosterone, and pro-inflammatory cytokines) in the brain, and the subsequent activation of the sympathetic nervous system, in a rat model of systolic heart failure. Learning more about the central nervous system mechanisms regulating sympathetic drive in heart failure may help identify novel approaches to the treatment of this devastating disorder.

描述（由申请人提供）：心力衰竭是美国 65 岁以上老年人住院的最常见原因，预计这一统计数据会随着人口老龄化而增长。交感神经系统（SNS）过度活动是心力衰竭综合征的主要表现，也是发病率和死亡率的有力预测因素。最近的研究表明，大脑中神经化学机制的改变导致心力衰竭中 SNS 活动的增强。心力衰竭时，大脑中会出现过量的几种兴奋性物质。这些包括血管紧张素 II (ANG II)、醛固酮 (ALDO) 和促炎细胞因子 (PIC)。这三种物质都会增加大脑中活性氧的产生，但除此之外，我们还不清楚它们如何激活 SNS。我们最近发现，阻断大脑中丝裂原激活蛋白激酶 (MAPK) 细胞内信号级联的三个主要成分之一，可显着降低心力衰竭大鼠的 SNS 活性。这些 MAPK 对活性氧的存在敏感，对 ANG II、ALDO 和 PIC 做出反应，并且在激活时会产生更多的兴奋性神经化学物质，这些物质可能有助于 SNS 的持续激活，这是心力衰竭的典型特征。该项目的总体目标是确定三种主要的 MAPK 信号通路在多大程度上对大脑关键心血管调节中心（下丘脑室旁核 (PVN)）中的兴奋性神经化学环境有贡献，该中心在心力衰竭中驱动 SNS 活动。在收缩性心力衰竭大鼠和正常大鼠中用ANG II、ALDO和PIC诱导MAPK活性，我们将确定：1）三大MAPK信号通路对PVN中兴奋性介质表达的影响； 2）PVN中MAPK信号传导对SNS活动的影响； 3) PVN 中表达 MAPK 信号的细胞（神经元、小胶质细胞、星形胶质细胞和血管周围巨噬细胞）的表型，及其对兴奋性介质和交感神经兴奋产生的影响。将结合分子、免疫组织化学和电生理学技术来阐明大脑 MAPK 信号传导影响 SNS 活动的机制。我们希望这些研究能够确定收缩性心力衰竭治疗干预的新靶点。 公共健康相关性：该项目研究了收缩性心力衰竭大鼠模型中关键的细胞内信号传导机制（丝裂原激活蛋白激酶）在大脑中兴奋性介质（血管紧张素 II、醛固酮和促炎细胞因子）上调以及随后交感神经系统激活中的作用。更多地了解心力衰竭中调节交感神经驱动的中枢神经系统机制可能有助于找到治疗这种破坏性疾病的新方法。