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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Wang, Lan-Hsiang
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University of Nebraska Medical Center
Emergency Medicine
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United States
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Tu, Huiyin; Zhang, Dongze; Li, Yu-Long (2018) Cellular and Molecular Mechanisms Underlying Arterial Baroreceptor Remodeling in Cardiovascular Diseases and Diabetes. Neurosci Bull :
Li, De-Pei; Li, Yu-Long; Li, Jianhua et al. (2017) Neural Mechanisms of Autonomic Dysfunction in Neurological Diseases. Neural Plast 2017:2050191
Li, Yu-Long; Zhang, Dongze; Tu, Huiyin et al. (2016) Altered ENaC is Associated With Aortic Baroreceptor Dysfunction in Chronic Heart Failure. Am J Hypertens 29:582-9
Zhang, Dongze; Muelleman, Robert L; Li, Yu-Long (2015) Angiotensin II-superoxide-NF?B signaling and aortic baroreceptor dysfunction in chronic heart failure. Front Neurosci 9:382
Zhang, Dongze; Liu, Jinxu; Zheng, Hong et al. (2015) Effect of angiotensin II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats. J Hypertens 33:1401-10
Tu, Huiyin; Liu, Jinxu; Zhang, Dongze et al. (2014) Heart failure-induced changes of voltage-gated Ca2+ channels and cell excitability in rat cardiac postganglionic neurons. Am J Physiol Cell Physiol 306:C132-42
Zhang, Dongze; Liu, Jinxu; Tu, Huiyin et al. (2014) In vivo transfection of manganese superoxide dismutase gene or nuclear factor ?B shRNA in nodose ganglia improves aortic baroreceptor function in heart failure rats. Hypertension 63:88-95
Li, Yu-Long (2013) Angiotensin II-Superoxide Signaling and Arterial Baroreceptor Function in Type-1 Diabetes Mellitus. J Diabetes Metab Suppl 12:1-6
Liu, Jinxu; Tu, Huiyin; Zheng, Hong et al. (2012) Alterations of calcium channels and cell excitability in intracardiac ganglion neurons from type 2 diabetic rats. Am J Physiol Cell Physiol 302:C1119-27
Liu, Jinxu; Tu, Huiyin; Zhang, Dongze et al. (2012) Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells. BMC Neurosci 13:129

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