Cytokine-induced NeurohumoralExcitation in Heart Failure

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），其有助于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）的临床过程是渐进的，长期预后仍然令人沮丧，这表明其他介质可能参与NHE。目前，免疫介导的机制已被认为在HF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脑内细胞因子的激活。我们还发现，阻断细胞因子减弱了HF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，直接或通过与肾素-血管紧张素系统（RAS）的相互作用，有助于心力衰竭的NHE。本申请的具体目的是：1.外周细胞因子直接或通过与外周RAS的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内源性脑RAS产物的相互作用激活心力衰竭中的NHE。3.心脏交感神经传入参与脑细胞因子激活，导致心力衰竭时的NHE。本提案将集中于了解外周和中枢神经系统的影响，三种细胞因子（白细胞介素-1 β，肿瘤坏死因子-α和白细胞介素-6）和血管紧张素对NHE在HF的贡献。这将通过整合分子、细胞、电生理和体内（大鼠和小鼠HF模型）实验方法的组合来实现。HF中细胞因子和神经体液系统之间的中心联系可能导致更好地理解疾病过程的进展，并最终导致治疗HF的新的有效策略。

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.