Cytokines and Sympathetic Activation in Heart Failure

心力衰竭中的细胞因子和交感神经激活

• 批准号: 7751935
• 负责人: Robert B Felder
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7751935
• 关键词: Address; Adverse effects; Age; Americas; Angiotensin II; Angiotensinogen; Angiotensins; Apoptosis; Arrhythmia; Automobile Driving; Binding; Binding Proteins; Blood; Blood Circulation; Brain; Brain region; Cardiac; Cardiovascular system; Cerebrospinal Fluid; Chronic; Clinical; Clinical Research; Clinical Trials; Critiques; Data; Dinoprostone; Disease; Dose; Enzymes; Etanercept; Etiology; Europe; Exclusion; Family; Goals; Healed; Health; Heart; Heart failure; Hospitalization; Human; Hypothalamic structure; Immune system; Industry; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intervention; Investigation; Ischemia; Kidney; Left Ventricular Function; Life; Literature; Lymphoma; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Morbidity - disease rate; Myocardial dysfunction; NADP; NF-kappa B; Nail plate; Nerve; Neuraxis; Neurons; Nuclear; Oxidases; Patients; Pericytes; Peripheral; Plasma; Population; Preventive Intervention; Process; Production; Prosencephalon; Prostaglandins; Protein Precursors; Proteins; Publishing; Rattus; Reactive Oxygen Species; Regimen; Renaissance; Renin; Renin-Angiotensin System; Research; Role; Severity of illness; Source; Stimulus; Superoxides; Sympathetic Nervous System; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor Necrosis Factor-alpha; United States; Work; adverse outcome; brain tissue; cyclooxygenase 2; cytokine; healing; human old age (65+); infliximab; insight; member; mortality; neurochemistry; neuromechanism; novel; novel strategies; paraventricular nucleus; public health relevance; receptor; statistics; transcription factor; vasoconstriction

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. Overactivity of the sympathetic nervous system is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. The etiology of increased sympathetic activity in heart failure is multifactorial. Recent studies have implicated inflammatory mechanisms that generate reactive oxygen species, particularly activation of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase dependent superoxide, in cardiovascular regions of the brain. The ability of angiotensin II to generate superoxide and sympathetic drive by this mechanism has been well studied - almost to the exclusion of other inflammatory mediators that are also increased in heart failure and might well contribute. The present project examines the potential role of the pro- inflammatory cytokines, which increase in plasma and brain of rats with ischemia-induced heart failure, are capable of NAD(P)H oxidase driven superoxide production, and are known to contribute to increased sympathetic drive in heart failure. We will test three hypotheses with regard to the mechanisms by which pro- inflammatory cytokines might activate the sympathetic nervous system in a rat model of ischemia-induced heart failure that mimics the most common form of heart failure in humans: 1) pro-inflammatory cytokines increase sympathetic nerve activity in heart failure rats by inducing cyclooxygenase-2 activity and the production of prostaglandin E2, which is sympatho-excitatory in the brain; 2) pro-inflammatory cytokines increase sympathetic nerve activity in heart failure rats by upregulating the brain renin-angiotensin system and the production of angiotensin II, which is sympatho-excitatory in the brain in its own right as well as by stimulating superoxide production; and 3) pro-inflammatory cytokines directly stimulate NAD(P)H oxidase dependent superoxide production. This project focuses upon the actions of pro-inflammatory cytokines in the paraventricular nucleus of the hypothalamus, a forebrain cardiovascular regulatory center that has been identified as an important source of the increased sympathetic nerve activity in heart failure. Neurochemical changes in the paraventricular nucleus in heart failure, and the cellular and molecular mechanisms which regulate them, will be investigated using molecular and immunohistochemical/immunofluorescent methods, and the results of those studies will be correlated with functional data from electrophysiological studies examining the effects of manipulating key putative mediators of sympathetic nerve activity. These studies will identify currently unrecognized mechanisms driving the sympathetic nervous system in heart failure, and thus potential targets for preventive intervention. PUBLIC HEALTH RELEVANCE: New approaches are needed to treat heart failure, which remains a devastating disorder despite current therapy. One aspect of heart failure that is not treated and is still poorly understood is the inflammatory response, manifest primarily by an increase in circulating pro-inflammatory cytokines. This project seeks to determine how inflammation contributes to activation of the sympathetic nervous system - a marker of adverse outcome in heart failure - and to discover novel ways of reducing its impact.

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。交感神经系统过度活跃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指标。心力衰竭交感神经活性增强的病因是多因素的。最近的研究表明，炎症机制会在大脑的心血管区域产生活性氧物种，特别是激活依赖于NAD(P)H氧化酶的超氧化物歧化酶。血管紧张素II通过这一机制产生超氧化物和交感神经驱动的能力已经得到了很好的研究-几乎排除了其他炎症介质，这些介质也会在心力衰竭中增加，并可能起到很好的作用。本项目研究了促炎细胞因子的潜在作用，这些细胞因子增加了缺血诱导的心力衰竭大鼠血浆和脑中的含量，能够产生NAD(P)H氧化酶驱动的超氧化物歧化，并被认为有助于心力衰竭中交感神经驱动的增加。在模拟人类最常见的心力衰竭的缺血型心力衰竭大鼠模型中，我们将测试三种关于促炎细胞因子激活交感神经系统的机制的假说：1)促炎细胞因子通过诱导环氧合酶-2活性和产生前列腺素E_2来增加心力衰竭大鼠的交感神经活性，前列腺素E_2在大脑中是交感兴奋的；2)促炎细胞因子通过上调脑肾素-血管紧张素系统和血管紧张素II的产生来增加心力衰竭大鼠的交感神经活性，血管紧张素II本身就是交感兴奋的，同时通过刺激超氧化物的产生；3)促炎细胞因子直接刺激NAD(P)H氧化酶依赖的超氧化物歧化酶的产生。本项目的重点是下丘脑室旁核中促炎细胞因子的作用，下丘脑室旁核是一个前脑心血管调节中心，已被确认为心力衰竭时交感神经活动增加的重要来源。将使用分子和免疫组织化学/免疫荧光方法研究室旁核在心力衰竭中的神经化学变化，以及调节这些变化的细胞和分子机制，这些研究的结果将与电生理学研究的功能数据相关联，这些研究旨在检验操纵交感神经活动的关键假定介质的效果。这些研究将确定目前尚不清楚的心力衰竭中驱动交感神经系统的机制，从而确定预防干预的潜在目标。与公共卫生相关：需要新的方法来治疗心力衰竭，尽管目前的治疗方法仍然是一种毁灭性的疾病。心力衰竭的一个方面没有得到治疗，也仍然知之甚少，那就是炎症反应，主要表现为循环中促炎症细胞因子的增加。这个项目试图确定炎症如何促进交感神经系统的激活--交感神经系统是心力衰竭不良后果的标志--并发现减少其影响的新方法。