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

描述（由申请人提供）：临床和动物研究已证实动脉压力感受性反射受损对慢性心力衰竭（CHF）的预后和死亡率的影响。然而，压力反射功能障碍的机制仍不清楚。由动脉压力感受器（AB）神经元组成的传入支作为压力反射的主要成分，参与了CHF状态下压力反射敏感性的减弱。众所周知，这些压力感受器神经元的压力敏感性在CHF中是钝化的。这种迟钝的敏感性通常被认为是由感觉末梢的机械传导受损引起的。然而，压力感受器神经元的细胞膜的电（电缆）特性的变化也可能有助于抑制兴奋性。基于我们的初步数据，我们假设，降低表达和激活的电压门控钠（Nav）通道有助于抑制AB神经元兴奋性和钝性主动脉压力反射敏感性在CHF。我们进一步假设，血管紧张素II（AngII）-超氧化物信号介导的这些变化的Nav通道功能。为了验证这一假设，我们建议在假手术和心肌梗死诱导的CHF大鼠中进行整体动物（主动脉压力感受器反射）、细胞（AB神经元中的动作电位和Nav通道记录）和分子（mRNA/蛋白表达、核因子-κ B与Nav通道启动子的结合、siRNA和腺病毒cDNA转染）研究的体内和体外研究。在具体目标1中，我们将研究CHF诱导的Nav电流和AB神经元兴奋性改变与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-κ B抑制CHF大鼠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型受体的过表达，并通过NADPH氧化酶和线粒体功能障碍介导超氧化物的过度产生，随后影响CHF大鼠的Nav通道功能、神经元兴奋性和主动脉压力感受器反射敏感性。总之，这些研究将为CHF中压力反射受损的机制提供新的信息，也将揭示改善压力反射功能和降低CHF死亡率的重要药理学和基因组靶点。 公共卫生相关性：结状神经节中的主动脉压力感受器（AB）神经元的功能障碍涉及慢性心力衰竭（CHF）的并发症动脉压力感受器反射损害。本项目主要研究CHF时AB神经元电兴奋性降低的信号转导机制。我们认为内源性血管紧张素II-超氧化物信号级联降低了钠通道功能和AB神经元的细胞兴奋性，从而导致CHF状态下压力感受性反射的钝化。这些研究的意义在于为CHF患者压力感受性反射功能障碍的正常化和降低死亡率提供新的策略。

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.