Cytokine-induced Neurohumoral Excitation in Heart Failure

心力衰竭中细胞因子诱导的神经体液兴奋

基本信息

批准号：
7269498
负责人：
JOSEPH FRANCIS
金额：
$ 33.85万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-15 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7269498
关键词：
Agonist Angiotensin II Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensins Animals Attenuated Biochemical Biological Brain Cardiac Cardiovascular system Chemicals Chronic Clinical Congestive Heart Failure Cytokine Activation Data Disease Disease Progression Doctor of Philosophy Electric Stimulation Equilibrium Fluid Balance Functional disorder Heart Heart Block Heart failure Hormones Hypothalamic structure Immune Immunohistochemistry In Situ Hybridization Individual Infarction Infusion procedures Interleukin-1 alpha Interleukin-1 beta Interleukin-6 Kidney Knockout Mice Lasers Lead Left Ventricular Dysfunction Light Link Liquid substance Measures Mediating Mediator of activation protein Messenger RNA Microscopy Mineralocorticoid Receptor Molecular Morbidity - disease rate Mus Myocardial Infarction Myocardium Names Nerve Neuraxis Neurohormones Numbers Pathogenesis Pathway interactions Patients Peptides Perfusion Peripheral Plasma Play Process Proteins Pulmonary Edema Rattus Regulation Renin Renin-Angiotensin System Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Role playing therapy Sodium Spironolactone Staging System Therapeutic Third ventricle structure Time Time Study Tissues Tumor Necrosis Factor-alpha Ventricular Remodeling Water base cytokine in vivo inhibitor/antagonist mortality mouse model outcome forecast paraventricular nucleus receptor

项目摘要

DESCRIPTION (provided by applicant): Chronic congestive heart failure is characterized by neurohumoral excitation (NHE) that contributes to the progression of end-stage disease and the premature demise of the patient. In the past few decades, most of the therapeutic measures were targeted against the activation of the neurohormonal system, and these strategies have clearly reduced mortality and morbidity. However, the clinical course of heart failure (HF) is progressive and the long-term prognosis remains dismal, suggesting that other mediators might be involved in NHE. Currently, immune mediated mechanisms have been recognized to play an important role in the pathogenesis of HF. Recently, we reported for the first time that cytokines are activated in the brain early after myocardial infarction. We also showed that blockade of cytokines attenuated NHE and angiotensin II receptor protein in the hypothalamus and the heart of HF rats. Therefore, we hypothesize that cytokines, acting either directly or via an interaction with the renin-angiotensin system (RAS), contribute to NHE in heart failure. The specific aims of this application are: 1. Peripheral cytokines drive NHE in heart failure, either directly or via an interaction with the peripheral RAS. 2. Central nervous system cytokines activate NHE in heart failure, either directly or via an interaction with products of intrinsic brain RAS. 3. Cardiac sympathetic afferents contribute to brain cytokine activation and bring about NHE in heart failure. This proposal will focus on understanding the contribution of peripheral and central nervous system influences of three cytokines (interleukin-1beta, tumor necrosis factor-alpha and interleukin-6) and angiotensin on NHE in HF. This will be accomplished by integrating a combination of molecular, cellular, electrophysiological and in vivo (rat and mouse model of HF) experimental approaches. The central link between cytokines and the neurohumoral system in HF may lead to a better understanding of the progression of the disease process and ultimately lead to new and effective strategies to treat HF.

描述（由申请人提供）：慢性充血性心力衰竭的特征是神经体液兴奋（NHE），其导致终末期疾病的进展和患者的过早死亡。在过去的几十年里，大多数治疗措施都是针对神经激素系统的激活，这些策略明显降低了死亡率和发病率。然而，心力衰竭 (HF) 的临床病程是进行性的，长期预后仍然不佳，这表明其他介质可能参与 NHE。目前，免疫介导机制已被认为在心力衰竭的发病机制中发挥重要作用。最近，我们首次报道了心肌梗死后早期大脑中细胞因子的激活。我们还发现，细胞因子的阻断可减弱心衰大鼠下丘脑和心脏中的 NHE 和血管紧张素 II 受体蛋白。因此，我们假设细胞因子直接作用或通过与肾素-血管紧张素系统 (RAS) 相互作用，导致心力衰竭中的 NHE。该应用的具体目标是： 1. 外周细胞因子直接或通过与外周 RAS 相互作用驱动心力衰竭中的 NHE。 2. 中枢神经系统细胞因子直接或通过与脑内 RAS 产物的相互作用激活心力衰竭中的 NHE。 3.心脏交感神经传入有助于脑细胞因子激活并导致心力衰竭的NHE。该提案将重点了解三种细胞因子（白细胞介素 1β、肿瘤坏死因子 α 和白细胞介素 6）和血管紧张素对心力衰竭 NHE 的外周和中枢神经系统影响的贡献。这将通过整合分子、细胞、电生理学和体内（心力衰竭的大鼠和小鼠模型）实验方法的组合来实现。心力衰竭中细胞因子和神经体液系统之间的中心联系可能有助于更好地了解疾病过程的进展，并最终导致治疗心力衰竭的新的有效策略。