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：
8099063
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/8099063
关键词：
Action Potentials Affect Angiotensin II Animals Attenuated Baroreflex Binding Canis familiaris Cell physiology Cells Cellular Membrane Chronic Clinical Complementary DNA Complex Complication Copper Cytosol Data Depressed mood Fiber 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 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）：临床和动物研究证实了动脉压力反射障碍对慢性心力衰竭的预后和死亡率（CHF）的贡献。然而，尚不清楚降压力反射功能障碍的机制尚不清楚。作为压力反射的主要成分，由动脉压力感受器（AB）神经元组成的传入肢体参与了CHF状态下的降低压力反射敏感性。众所周知，这些压力感受器神经元的压力灵敏度在CHF中被钝化。通常假定这种钝的灵敏度是由于感觉终端的机械转移损害造成的。但是，压力感受器神经元的细胞膜的电（电缆）特性的变化也可能导致抑制性兴奋性。基于我们的初步数据，我们假设电压门控钠（NAV）通道的表达和激活减少有助于CHF中抑郁的AB神经元兴奋性，并使主动脉动脉baroreflex敏感性钝化。我们进一步假设血管紧张素II（ANGII） - 超氧化物信号传导介导了NAV通道功能中的这些变化。 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.在特定的目标1中，我们将研究CHF诱导的NAV电流变化以及AB神经元和主动脉降压敏感性的兴奋性之间的关系。在特定的目标2中，我们建议内源性超氧化物过量产生通过损害AB神经元通道活性以及通过核因子-kappa B抑制CHF大鼠中NAV通道表达的介导这些改变。最后，我们在特定的目标3中提出，Angii的升高和Angii 1型受体的过表达发生在CHF大鼠鼻神经节中，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，并随后影响NAVER型兴奋性，Neuron兴奋性，Neuron兴奋性，和主动脉barore baroreflex sextielitive。综上所述，这些研究将提供有关CHF中压力反射受损的机制的新信息，并将推出重要的药理学和基因组靶标，以改善CHF中的压力反射功能和降低死亡率。公共卫生相关性：Nodose神经节中主动脉压力感受器（AB）神经元的功能障碍参与动脉压力反射障碍，这是慢性心力衰竭（CHF）的并发症。该项目着重于CHF中AB神经元的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-塞氧化物信号传导级联反应降低AB神经元的钠通道功能和细胞兴奋性，随后在CHF状态下有助于钝化的Baroreflex。这些研究的意义是提供一种新的策略，以使压力反射功能障碍正常化并降低CHF的死亡率。