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，这一统计数据预计会增长。交感神经系统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一个强有力的预测指标。心衰患者交感神经活动增加的病因是多因素的。最近的研究表明，炎症机制可能产生活性氧，特别是脑心血管区烟酰胺腺嘌呤二核苷酸磷酸[NAD(P)H]氧化酶依赖性超氧化物的激活。血管紧张素II通过这种机制产生超氧化物和交感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，这些炎症介质也在心力衰竭中增加，并且可能有很大的贡献。本项目研究了促炎细胞因子的潜在作用，促炎细胞因子在缺血性心力衰竭大鼠的血浆和脑中增加，能够产生NAD(P)H氧化酶驱动的超氧化物，并且已知有助于增加心力衰竭的交感驱动。我们将在模拟人类最常见的心力衰竭的缺血性心力衰竭大鼠模型中测试关于促炎细胞因子可能激活交感神经系统的机制的三个假设：1)促炎细胞因子通过诱导环氧化酶-2活性和前列腺素E2的产生来增加心力衰竭大鼠的交感神经活性，前列腺素E2在大脑中具有交感神经兴奋性；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的产生增加心力衰竭大鼠的交感神经活动，血管紧张素II本身在大脑中具有交感-兴奋作用，并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氧化酶依赖性超氧化物的产生。本项目关注促炎细胞因子在下丘脑室旁核中的作用，下丘脑室旁核是前脑心血管调节中心，已被确定为心力衰竭交感神经活动增加的重要来源。心衰时室旁核的神经化学变化，以及调节这些变化的细胞和分子机制，将使用分子和免疫组织化学/免疫荧光方法进行研究，这些研究的结果将与电生理学研究的功能数据相关联，这些研究检查了操纵交感神经活动的关键介质的影响。这些研究将确定目前尚未认识的驱动交感神经系统心力衰竭的机制，从而确定预防性干预的潜在目标。公共卫生相关性：需要新的方法来治疗心力衰竭，尽管目前的治疗仍然是一种毁灭性的疾病。心衰的一个方面没有得到治疗，并且仍然知之甚少，那就是炎症反应，主要表现为循环中促炎细胞因子的增加。该项目旨在确定炎症如何促进交感神经系统的激活-这是心力衰竭不良结果的标志-并发现减少其影响的新方法。