Altered CNS intercellular signaling mechanisms in cardiovascular disease

  • Stern, Javier Eduardo, (PI)

Project: Research project

Description

DESCRIPTION (provided by applicant): Neurohumoral activation, characterized by elevated sympathetic tone, blunted cardiovascular reflexes, and elevated hormonal plasma levels, is a common finding in a variety of cardiovascular diseases, including hypertension and heart failure (HF). Despite compelling evidence supporting increased neurohumoral drive as a major determinant of patients' prognosis and mortality, none of the current therapeutic strategies efficiently inhibit neurohumoral activation, failing thus to improve the survival or stop the progression of these cardiovascular diseases. Although altered central autonomic function plays an important role in the pathophysiology of major cardiovascular diseases, the precise cellular mechanisms underlying such alteration are still poorly understood. Recent studies from our laboratories indicate that neuronal activation within the hypothalamic paraventricular nucleus (PVN), one of the major preautonomic and neuroendocrine brain centers, contributes to elevated neurohumoral drive in cardiovascular disease states. Here, using a multidisciplinary approach that ranges from the whole animal to single molecules, we propose to use the PVN central neuronal circuitry and a rat model of ischemic HF to test a series of novel hypotheses that aim to unveil basic mechanistic principles involved in the central control of cardiovascular function in health and disease conditions. Specifically, we propose a model in which PVN glutamate tripartite synapses represented by glutamate (GLU) synaptic inputs, postsynaptic sympathetic PVN neurons, and associated astrocytes, constitute key structural/functional units fine-tuning PVN neuronal excitability and sympathetic output. We hypothesize that altered intercellular communication within this unit contributes to enhanced neuronal excitability and sympathoexcitation during HF. We propose that during HF, structural/functional reconfiguration of GLU afferent inputs, changes in GLU receptor portfolios, and changes in neuronal-glial interactions favors excitatory (direct excitatory GLU action) (Aims 1-3) over inhibitory (GLU-mediated nitric oxide-GABA action) (Aim 4) pathways within the PVN tripartite functional unit. The proposed experiments will identify the underlying pre-, post- ad extrasynaptic mechanisms contributing to elevated PVN neuronal excitability and elevated neurohumoral drive during HF. In addition, we will test the general novel hypothesis that hypothalamic astrocytes efficiently modulate PVN neuronal and synaptic function, as well as sympathoexcitatory drive in health and disease conditions. Overall, this project will provide critical and novel information on mechanisms controlling neuronal excitability and intercellular communication within a fundamental preautonomic brain center involved in the central control of cardiovascular function, and will unveil specific pathophysiological mechanisms underlying neurohumoral activation in cardiovascular diseases.
StatusFinished
Effective start/end date1/15/086/30/18

Funding

  • National Institutes of Health: $402,144.00
  • National Institutes of Health: $374,300.00
  • National Institutes of Health: $367,884.00
  • National Institutes of Health: $15,622.00
  • National Institutes of Health: $388,056.00
  • National Institutes of Health: $371,486.00
  • National Institutes of Health: $362,200.00

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Paraventricular Hypothalamic Nucleus
Cardiovascular Diseases
Heart Failure
Glutamic Acid
Astrocytes
N-Methyl-D-Aspartate Receptors
N-Methylaspartate
gamma-Aminobutyric Acid
Health
Glutamate Receptors
Brain
Nitric Oxide
Neurons
Neuroglia
Synapses
Reflex
Mortality
Mitochondria
Hypertension
Survival

ASJC

  • Medicine(all)