Cytokine and sympathetic drive in heart failure

心力衰竭中的细胞因子和交感神经驱动

• 批准号: 6704843
• 负责人: Robert B Felder
• 金额: $ 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: 2003-01-21 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704843
• 关键词: angiotensin receptor; catecholamines; electrophysiology; free radical oxygen; heart failure; heart innervation; immunocytochemistry; interleukin 1; laboratory rat; myocardial ischemia /hypoxia; neuroregulation; paraventricular nucleus; renin angiotensin system; sympathetic nervous system; tumor necrosis factor alpha

Immune system activation (ISA) is a commonly recognized component of the heart failure syndrome. The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-lbeta)- the blood borne products of ISA- activate the sympathetic nervous system. The overall hypothesis of this project is that these pro-inflammatory cytokines contribute to the augmented sympathetic drive in heart failure by their actions upon neurons in the paraventricular nucleus (PVN) of the hypothalamus. Two principal mechanisms for this proposed effect will be investigated. 1) Circulating cytokines induce catecholamine release in PVN. Increased catecholamine content in PVN has been associated with heightened sympathetic drive in other pathophysiologicalconditions, such as neurogenic hypertension, that are also characterized by increased activity of the renin-angiotensinsystem (RAS). The present studies will examine the hypothesis that catecholamine release in PVN, induced by circulating cytokines, activates sympatho-excitatory PVN neurons, and that this effect is facilitated by interactions in PVN between catecholamines and the RAS. 2) Cytokines induce the production of reactive oxygen species (ROS). Cytokines may be produced in the brain, and may enter the brain via a saturable membrane transport system. The present studies will examine the hypothesisthat in heart failure the presence of cytokines in the PVN induces ROS, which activates sympatho-excitatory PVN neurons. Finally, these studies will examine the mechanisms by which activation of PVN neurons by circulating or intrinsic cytokines might elicit an increase in sympathetic drive. Recent evidence suggests that signals descending from PVN require activation of an angiotensin type 1 receptor in rostral ventrolateral medulla (RVLM) to effect an increase in sympathetic drive. The present studies will determine whether sympatho-excitatoryPVN neurons activated by pro-inflammatory cytokines utilize this pathway. Electrophysiologicalrecordingtechniques will be used in conjunction with push-pull analysis of peptide/transmitter release and immunohistochemistry to test these hypotheses in rats with ischemia-induced heart failure and in sham-operated controls. These studies will provide important new insightsinto the role of the pro-inflammatorycytokines in heart failure.

免疫系统激活（ISA）是心力衰竭综合征的一个公认的组成部分。 促炎细胞因子肿瘤坏死因子-α (TNF-α) 和白细胞介素-1 β (IL-1β)（ISA 的血液传播产物）可激活交感神经系统。 该项目的总体假设是，这些促炎细胞因子通过作用于下丘脑室旁核（PVN）的神经元，从而增强心力衰竭的交感神经驱动。 将研究这种拟议效应的两个主要机制。 1) 循环细胞因子诱导 PVN 中儿茶酚胺的释放。 PVN 中儿茶酚胺含量的增加与其他病理生理状况（例如神经源性高血压）中交感神经驱动力的增强有关， 其特征还在于肾素-血管紧张素系统（RAS）活性增加。 目前的研究将检验以下假设：由循环细胞因子诱导的PVN中儿茶酚胺释放激活交感神经兴奋性PVN神经元，并且这种效应是由PVN中儿茶酚胺和RAS之间的相互作用促进的。 2）细胞因子诱导活性氧（ROS）的产生。 细胞因子可以在大脑中产生，并且可以通过可饱和膜运输系统进入大脑。 目前的研究将检验以下假设：在心力衰竭中，PVN 中细胞因子的存在会诱导 ROS，从而激活交感兴奋性 PVN 神经元。 最后，这些研究将检验 循环或内在细胞因子激活 PVN 神经元可能引起交感神经驱动增加的机制。最近的证据表明，PVN 发出的信号需要激活延髓头端腹外侧 (RVLM) 中的 1 型血管紧张素受体，以增强交感神经驱动。 目前的研究将确定促炎细胞因子激活的交感兴奋性PVN神经元是否利用该途径。电生理记录技术将与肽/递质释放的推拉分析和免疫组织化学结合使用，以在缺血性心力衰竭大鼠和假手术对照中测试这些假设。 这些研究将 为促炎细胞因子在心力衰竭中的作用提供了重要的新见解。