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.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Lathrop, David A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia Regents University
Schools of Medicine
United States
Zip Code
Stern, J E; Filosa, J A (2013) Bidirectional neuro-glial signaling modalities in the hypothalamus: role in neurohumoral regulation. Auton Neurosci 175:51-60
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
Son, Sook Jin; Filosa, Jessica A; Potapenko, Evgeniy S et al. (2013) Dendritic peptide release mediates interpopulation crosstalk between neurosecretory and preautonomic networks. Neuron 78:1036-49
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
Tasker, J G; Oliet, S H R; Bains, J S et al. (2012) Glial regulation of neuronal function: from synapse to systems physiology. J Neuroendocrinol 24:566-76
Biancardi, Vinicia C; Son, Sook J; Sonner, Patrick M et al. (2011) Contribution of central nervous system endothelial nitric oxide synthase to neurohumoral activation in heart failure rats. Hypertension 58:454-63
Han, Tae Hee; Lee, Kiho; Park, Jin Bong et al. (2010) Reduction in synaptic GABA release contributes to target-selective elevation of PVN neuronal activity in rats with myocardial infarction. Am J Physiol Regul Integr Comp Physiol 299:R129-39
Michelini, Lisete C; Stern, Javier E (2009) Exercise-induced neuronal plasticity in central autonomic networks: role in cardiovascular control. Exp Physiol 94:947-60