Molecular mechanisms of sympatho-excitation in cardiovascular disease

Project summary/abstract Cardiovascular disease is the leading cause of death worldwide, and overactivity of the sympathetic branch of the autonomic nervous system (sympatho-excitation) plays a key role in the pathogenesis or progression of numerous cardiovascular diseases. Overactivity of cardiac sympathetic neurons leads to increased release of neuropeptide Y (NPY), the major neuropeptide in the heart. Excess NPY release has been correlated with worse outcomes in heart failure, where it is speculated to be arrhythmogenic and contribute to sudden cardiac death. Our long-term goal is to understand what molecular changes occur within cardiac sympathetic neurons during sympatho-excitiation that contribute to the increased release of NPY in cardiovascular disease. The central hypothesis of this grant is that increased NPY levels in sympatho-excitation are attributable to enhanced trafficking, synaptic localization, and exocytic fusion of NPY-containing vesicles in postganglionic sympathetic neurons. These studies represent a major change in research direction for the investigator who previously studied neuropathic pain. We will utilize our novel high-resolution, live-cell imaging techniques developed to study the dynamic regulation of nociceptors, and adapt them to investigating the pathological regulation of the heart in cardiovascular disease. Using a compartmentalized chamber, we will co-culture sympathetic neurons from the superior cervical ganglia of neonatal rats with ventricular myocytes to form neuro-cardiac junctions. The central hypothesis will be tested using the following aims: 1) To observe the real-time relationship between sympathetic neuron firing rates and release of NPY, 2) To determine whether the formation of neuro-cardiac junctions enhances the trafficking of NPY-containing vesicles to and capture within synaptic varicosities, and 3) To determine whether sympathetic neurons from a neurogenic model of cardiovascular disease (spontaneously hypertensive rats; SHRs) exhibit increased baseline excitability, including increased release of NPY. The results of these innovative studies will represent the first report of the dynamic regulation of vesicular trafficking and neuropeptide release in sympathetic neurons, and could transform how we detect and treat some cardiovascular diseases.