Brain MAP Kinases - Substrate for Sympathetic Excitation in Heart Failure

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，随着人口老龄化，这一统计数据预计将会增长。交感神经系统(SNS)的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强烈预测因子。最近的研究表明，大脑中神经化学机制的改变有助于心力衰竭时SNS活性的增强。在心力衰竭时，大脑中会出现过量的几种兴奋性物质。这些物质包括血管紧张素II(Ang II)、醛固酮(Aldo)和促炎细胞因子(PIC)。这三种物质都能增加大脑中活性氧的产生，但除此之外，还完全不清楚它们是如何激活SNS的。我们最近发现，阻断大脑中丝裂原活化蛋白激酶(MAPK)细胞内信号级联的三个主要组成部分之一，可显著降低心力衰竭大鼠的SNS活性。这些MAPK对活性氧物种的存在很敏感，对Ang II、Aldo和PIC做出反应，当被激活时，导致更多兴奋性神经化学物质的产生，这可能有助于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个主要的MAPK信号通路在多大程度上对大脑的关键心血管调节中心--下丘脑室旁核(PVN)--的兴奋性神经化学环境做出贡献，在心力衰竭时，PVN驱动SNS活动。在收缩性心力衰竭大鼠和用Ang II、Aldo和PIC诱导MAPK活性的正常大鼠中，我们将确定：1)三条主要MAPK信号通路对PVN兴奋性介质表达的影响；2)PVN中MAPK信号对SNS活性的影响；3)PVN中表达MAPK信号的神经元、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产生和交感兴奋的影响。我们将结合分子、免疫组织化学和电生理学技术来阐明大脑MAPK信号影响SNS活性的机制。我们希望这些研究将为收缩性心力衰竭的治疗干预找到新的靶点。 公共卫生相关性：该项目在一种收缩性心力衰竭大鼠模型中，研究了一种关键的细胞内信号机制，即丝裂原激活的蛋白激酶，在脑内兴奋性介质(血管紧张素II、醛固酮和促炎细胞因子)的上调以及随后交感神经系统的激活中所起的作用。了解更多关于中枢神经系统调节心力衰竭交感神经驱动的机制可能有助于确定治疗这种毁灭性疾病的新方法。

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.