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

描述（由申请人提供）：临床和动物研究证实，动脉压力反射障碍对慢性心力衰竭（CHF）的预后和死亡率有影响。然而，压力反射功能障碍的机制尚不清楚。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中被钝化。这种迟钝的敏感性通常被认为是由于感觉末端的机械转导受损造成的。然而，压力感受器神经元细胞膜的电（电缆）特性的变化也可能有助于抑制兴奋性。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了CHF中AB神经元兴奋性降低和主动脉压力反射敏感性减弱。我们进一步假设血管紧张素II (AngII)-超氧化物信号介导了Nav通道功能的这些变化。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大鼠中进行全动物（主动脉压力反射）、细胞（AB神经元的动作电位和Nav通道记录）和分子（mRNA/蛋白表达、核因子κ B结合Nav通道启动子、siRNA和腺病毒cDNA转染）的体内和体外研究。在Specific Aim 1中，我们将研究chf诱导的Nav电流改变与AB神经元兴奋性和主动脉反射敏感性之间的关系。在Specific Aim 2中，我们提出内源性超氧化物过量通过损害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Specific Aim 3中提出，在CHF大鼠结节神经节中出现AngII升高和AngII型1受体的过度表达，并通过NADPH氧化酶和线粒体功能障碍介导超氧化物的过量产生，从而影响CHF大鼠的Nav通道功能、神经元兴奋性和主动脉反射敏感性。综上所述，这些研究将为心力衰竭中压力反射受损的机制提供新的信息，并将揭示改善压力反射功能和降低心力衰竭死亡率的重要药理学和基因组靶点。

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.