Dysfunction of Baroreceptor Neurons in Heart Failure: Cellular and Molecular Mech

心力衰竭中压力感受器神经元的功能障碍：细胞和分子机制

基本信息

批准号：
7985627
负责人：
Yu-Long Li
金额：
$ 37.13万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7985627
关键词：
Action Potentials Affect Angiotensin II Animals Attenuated Autonomic Dysfunction Baroreflex Binding Canis familiaris Cell physiology Cells Cellular Membrane Chronic Clinical Complementary DNA Complex Complication Copper Cytosol Data Depressed mood Fiber Figs - dietary Functional disorder Ganglia Genomics Heart failure Impairment In Vitro Ion Channel Kinetics Limb structure Manganese Superoxide Dismutase Mediating Mental Depression Messenger RNA Mitochondria Modeling Molecular Multienzyme Complexes Myocardial Infarction Myxoid cyst NADPH Oxidase NF-kappa B Nerve Neurons Nodose Ganglion Patients Pressoreceptors Production Property Protein Isoforms Proteins Rattus Receptor, Angiotensin, Type 1 Reflex action Research Design Role Sensory Signal Transduction Small Interfering RNA Sodium Sodium Channel Staining method Stains Superoxides Survival Rate System Techniques Testing Time Tissues Transfection Transgenes Western Blotting Zinc base chromatin immunoprecipitation copper zinc superoxide dismutase enzyme activity improved in vivo mitochondrial dysfunction mortality neuronal cell body outcome forecast overexpression patch clamp pressure promoter protein expression public health relevance receptor receptor expression research study sham surgery therapeutic target transcription factor voltage

项目摘要

DESCRIPTION (provided by applicant): Clinical and animal studies have confirmed a contribution of arterial baroreflex impairment to the prognosis and mortality of chronic heart failure (CHF). However, the mechanisms underlying baroreflex dysfunction remain unclear. As the primary component of the baroreflex, the afferent limb comprised of arterial baroreceptor (AB) neurons is involved in the attenuated baroreflex sensitivity in the CHF state. It is well known that the pressure sensitivity of these baroreceptor neurons is blunted in CHF. This blunted sensitivity generally has been assumed to result from an impairment of mechanotransduction at the sensory terminals. However, changes in the electrical (cable) properties of the cellular membrane of baroreceptor neurons also may contribute to suppressed excitability. Based upon our preliminary data, we hypothesize that reduced expression and activation of voltage-gated sodium (Nav) channels contributes to the depressed AB neuron excitability and blunted aortic arterial baroreflex sensitivity in CHF. We further hypothesize that angiotensin II (AngII)- superoxide signaling mediates these changes in Nav channel function. In order to test this hypothesis, we propose to perform in vivo and in vitro studies at the whole animal (aortic arterial baroreflex), cellular (action potential and Nav channel recording in AB neurons), and molecular (mRNA/protein expression, nuclear factor-kappa B binding to Nav channel promoter, siRNA, and adenoviral cDNA transfection) studies in sham and myocardial infarction-induced CHF rats. In Specific Aim 1, we will examine the relationship among CHF-induced alterations in Nav currents and excitability in AB neurons and aortic baroreflex sensitivity. In Specific Aim 2, we propose that endogenous superoxide over-production mediates these alterations by impairing AB neuron Nav channel activity, and through nuclear factor-kappa B suppression of Nav channel expression in CHF rats. Finally, we propose in Specific Aim 3 that elevation of AngII and over-expression of the AngII type 1 receptors occur in CHF rat nodose ganglia and mediate the superoxide over-production via NADPH oxidase and mitochondrial dysfunction and subsequently affect Nav channel function, neuron excitability, and aortic baroreflex sensitivity in CHF rats. Taken together, these studies will provide new information on the mechanisms underlying the impaired baroreflex in CHF and will also unveil important pharmacological and genomic targets for improving baroreflex function and reducing mortality in CHF. PUBLIC HEALTH RELEVANCE: Dysfunction of aortic baroreceptor (AB) neurons in nodose ganglia is involved in arterial baroreflex impairment, a complication of chronic heart failure (CHF). This project focuses on the signal transduction for lowered cell electrical excitability of AB neurons in CHF. We propose endogenous angiotensin II-superoxide signaling cascade decreases the sodium channel function and cell excitability of AB neurons and subsequently contributes to the blunted baroreflex in CHF state. The significance of these studies is to provide a new strategy to normalize the baroreflex dysfunction and to reduce mortality in CHF.

描述（由申请人提供）：临床和动物研究已证实动脉压力反射损伤对慢性心力衰竭（CHF）的预后和死亡率有影响。然而，压力感受反射功能障碍的机制仍不清楚。作为压力反射的主要组成部分，由动脉压力感受器 (AB) 神经元组成的传入肢参与 CHF 状态下压力反射敏感性的减弱。众所周知，CHF 时这些压力感受器神经元的压力敏感性减弱。通常认为这种敏感性减弱是由于感觉末端的机械传导受损造成的。然而，压力感受器神经元细胞膜电（电缆）特性的变化也可能导致兴奋性受到抑制。根据我们的初步数据，我们假设电压门控钠 (Nav) 通道的表达和激活减少导致 CHF 中 AB 神经元兴奋性降低和主动脉压力感受性反射敏感性减弱。我们进一步假设血管紧张素 II (AngII)-超氧化物信号传导介导 Nav 通道功能的这些变化。为了检验这一假设，我们建议对整个动物（主动脉压力反射）、细胞（AB 神经元中的动作电位和 Nav 通道记录）和分子（mRNA/蛋白质表达、核因子）进行体内和体外研究。 -kappa B 与 Nav 通道启动子的结合、siRNA 和腺病毒 cDNA 转染）在假手术大鼠和心肌梗死诱导的 CHF 大鼠中进行的研究。在具体目标 1 中，我们将检查 CHF 引起的 Nav 电流变化与 AB 神经元的兴奋性和主动脉压力反射敏感性之间的关系。在具体目标 2 中，我们提出内源性超氧化物过量产生通过损害 AB 神经元 Nav 通道活性以及通过核因子 kappa B 抑制 CHF 大鼠的 Nav 通道表达来介导这些改变。最后，我们在具体目标 3 中提出，CHF 大鼠结状神经节中发生 AngII 升高和 AngII 1 型受体过度表达，并通过 NADPH 氧化酶和线粒体功能障碍介导超氧化物过量产生，从而影响 Nav 通道功能、神经元兴奋性和 CHF 大鼠的主动脉压力反射敏感性。总而言之，这些研究将提供有关 CHF 压力反射受损机制的新信息，并将揭示改善 CHF 压力反射功能和降低死亡率的重要药理学和基因组靶点。公共卫生相关性：结状神经节中主动脉压力感受器 (AB) 神经元的功能障碍与动脉压力感受反射损伤有关，这是慢性心力衰竭 (CHF) 的并发症。该项目重点研究 CHF 中 AB 神经元细胞电兴奋性降低的信号转导。我们提出内源性血管紧张素 II-超氧化物信号级联会降低 AB 神经元的钠通道功能和细胞兴奋性，从而导致 CHF 状态下的压力反射减弱。这些研究的意义在于提供一种使压力感受反射功能正常化并降低 CHF 死亡率的新策略。