Neurohumoral activation, including sympathoexcitation and increased circulating hormonal levels such as vasopressin, is a major player in the pathophysiology of heart failure (HF), directly influencing morbidity and mortality i this disease. While the contribution of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei to neurohumoral activation in HF is established, a comprehensive understanding of the precise cellular mechanisms contributing to increased neuronal activity within these nuclei in HF remains elusive. Activity-dependent changes in neuronal intracellular Ca2+ levels (D[Ca2+]I)act as a critical signal influencing not only membrane excitability, but also neuroplasticity and gene expression. The excitatory transmitter glutamate, acting primarily via NMDA receptors (NMDAR), is a major source of D[Ca2+]I signaling (NMDA-DCa2+], playing an important role in the regulation of neurosecretory and presympathetic neuronal activity. Importantly, a growing body of evidence supports an exacerbated glutamate function in HF. Moreover, other signaling mechanisms that are directly linked to NMDA-DCa2+ (e.g, nitric oxide, ROS, GABA) are also altered in HF. The overall functional consequences of NMDA-DCa2+ are largely dependent on the spatiotemporal pattern of the D[Ca2+]I Thus, elucidating the precise mechanisms that influence the NMDA-DCa2+ properties, and how abnormal changes in these mechanisms may contribute to exacerbated neuronal activity in HF, is highly relevant. We have obtained exciting preliminary data supporting that mitochondria, classically viewed as static cellular power plants, are critical and dynamic organelles that actively influence NMDAR efficacy, by restraining its Ca2+-dependent coupling to other intracellular signaling pathways, influencing in turn overall SON/PVN neurosecretory and presympathetic neuronal activity. Moreover, we found that a blunted NMDAR- mitochondria crosstalk results in an enhanced NMDAR efficacy and exacerbated NMDA-DCa2+ leading to increased activation of the Ca2+- dependent family of TRP channels, and ultimately, abnormally elevated neuronal activity in HF. Here, we will test the central hypothesis that disruption of mitochondrial structurl-functional integrity results in exacerbated glutamate excitatory function, which via a strengthened coupling to Ca2+-sensitive TRPM4 channels, leads to enhanced neuronal activity in HF. This hypothesis will be tested in 3 specific aims: 1- To elucidate the role of mitochondria in shaping NMDAR-[Ca2+]i signaling in SON/PVN neurons, 2- To elucidate structural and functional mitochondrial mechanisms contributing to altered NMDAR-[Ca2+]i signaling in SON/PVN neurons HF rats, and 3- To determine the consequences of mitochondrial dysfunction on NMDAR-mediated neuronal excitability in HF rats. We expect results from this work to broaden our understanding of basic cellular mechanisms contributing to the hypothalamic regulation of neurohumoral outflows, and how changes in these mechanisms may contribute to neurohumoral activation in heart failure.

Public Health Relevance

Heart failure, a major public health problem in the USA, is characterized by increased activity of the neuroendocrine and autonomic systems (neurohumoral activation), which strongly influences morbidity and mortality in these patients. However, the precise mechanisms underlying neurohumoral remain unknown. In this proposal, we will use a multidisciplinary approach to test a series of novel hypothesis that aim to elucidate signaling mechanisms within the central nervous system that contribute to neurohumoral activation in heart failure. We expect our work to provide novel information on mechanisms underlying altered neuronal function in heart failure patients, and to help in the development of novel and more efficient therapeutic strategies for the treatment of this prevalent disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090948-07
Application #
8845593
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Lathrop, David A
Project Start
2008-01-15
Project End
2018-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Ferreira-Neto, Hildebrando C; Biancardi, Vinicia C; Stern, Javier E (2017) A reduction in SK channels contributes to increased activity of hypothalamic magnocellular neurons during heart failure. J Physiol 595:6429-6442
de Kloet, Annette D; Pitra, Soledad; Wang, Lei et al. (2016) Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice. Endocrinology 157:3167-80
Stern, Javier E; Son, Sookjin; Biancardi, Vinicia C et al. (2016) Astrocytes Contribute to Angiotensin II Stimulation of Hypothalamic Neuronal Activity and Sympathetic Outflow. Hypertension 68:1483-1493
Pitra, Soledad; Feng, Yumei; Stern, Javier E (2016) Mechanisms underlying prorenin actions on hypothalamic neurons implicated in cardiometabolic control. Mol Metab 5:858-68
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Stern, Javier E; Potapenko, Evgeniy S (2013) Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats. Am J Physiol Regul Integr Comp Physiol 305:R414-22
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Reis, W L; Biancardi, V C; Son, S et al. (2012) Enhanced expression of heme oxygenase-1 and carbon monoxide excitatory effects in oxytocin and vasopressin neurones during water deprivation. J Neuroendocrinol 24:653-63

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