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Cytokines and Sympathetic Activation in Heart Failure

心力衰竭中的细胞因子和交感神经激活

基本信息

批准号：
8389884
负责人：
Robert B Felder
金额：
$ 35.34万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389884
关键词：
Address Adverse effects Age Americas Angiotensin II Angiotensinogen 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 Nerve Neuraxis Neurons Nuclear Oxidases Patients Pericytes Peripheral Plasma Population Preventive Intervention Process Production Prosencephalon Prostaglandins Protein Precursors Proteins Publishing Rattus Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regimen Renin Renin-Angiotensin System Research Role Severity of illness Source Stimulus Superoxides Sympathetic Nervous System Syndrome TNF gene Testing Therapeutic Therapeutic Intervention Tissues Tumor Necrosis Factor-alpha United States Work abstracting adverse outcome brain tissue cyclooxygenase 2 cytokine healing human old age (65+)infliximab insight member mortality neurochemistry neuromechanism novel novel strategies paraventricular nucleus receptor statistics transcription factor vasoconstriction

项目摘要

6. Project Summary/Abstract 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.

6.项目摘要/摘要心力衰竭是美国65岁以上老年人住院的最常见原因这一统计数字预计将随着人口老龄化而增长。交感神经过度活跃系统是心力衰竭综合征的主要表现，也是发病率和死亡率。心力衰竭交感神经活性增强的病因是多因素的。最近的研究表明与产生活性氧有关的炎症机制，特别是激活心血管中的烟酰胺腺嘌呤二核苷酸磷酸[NAD(P)H]氧化酶依赖的超氧化物歧化酶大脑的不同区域。血管紧张素II产生超氧化物的能力和由此产生的交感神经驱动机制已经被很好地研究了-几乎排除了其他也是心力衰竭的增加，这很可能是原因之一。本项目审查了PRO的潜在作用- 在缺血性心力衰竭大鼠的血浆和脑中增加的炎性细胞因子是能够由NAD(P)H氧化酶驱动的超氧化物产生，并已知有助于增加心力衰竭时的交感神经驱动力。我们将检验三个关于PRO的机制的假说。炎性细胞因子对大鼠脑缺血模型交感神经系统的激活作用与人类最常见的心力衰竭形式相似的心力衰竭：1)促炎细胞因子诱导环氧合酶-2活性增强心力衰竭大鼠交感神经活性产生前列腺素E_2，它在大脑中是交感兴奋的；2)促炎细胞因子上调脑肾素-血管紧张素系统增强心力衰竭大鼠交感神经活性血管紧张素II的产生，它本身在大脑中是交感兴奋的，也是通过刺激超氧化物生成；3)促炎细胞因子直接刺激NAD(P)H氧化酶依赖于超氧化物的产生。该项目重点研究促炎细胞因子在血管内皮细胞中的作用。下丘脑室旁核，一个前脑心血管调节中心，一直是被认为是心力衰竭时交感神经活性增加的重要来源。神经化学心力衰竭时室旁核的变化及其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研究的功能数据相关联检查操纵交感神经活动的关键假定中介的效果。这些研究将确定目前尚不清楚的心力衰竭交感神经系统的驱动机制预防性干预的潜在目标。