Changes in sympathetic neurotransmission after myocardial infarction are a leading contributor to cardiac arrhythmia, sudden cardiac death, and heart failure, which are leading causes of mortality in the United States. The long term goal of the proposed research is to understand the molecular basis for altered sympathetic transmission following infarction. Regional changes in tyrosine hydroxylase (TH) and the norepinephrine transporter (NET) in the post-infarct cardiac innervation may be responsible for the contradictory observations that functional denervation and depletion of neuronal norepinephrine (NE) are accompanied by increased extracellular NE. Above the infarct, TH is elevated while NET is unchanged, leading to a pathological buildup of extracellular NE. In contrast, both are suppressed in the peri-infarct left ventricle, and the infarct is devoid of nerve fibers, resulting in the loss of transmission. Preliminary data suggest that cytokines and sympathetic nerve activity cause the regional changes in TH and NET that lead to heterogeneity in neurotransmission in the heart. Cardiotrophin-1 related cytokines are elevated in the heart after infarction. These cytokines suppress noradrenergic function in non-cardiac sympathetic neurons. Infarction also causes activation of the sympathetic nervous system, which stimulates TH, NE synthesis, and to a lesser degree, NET. This leads to the hypothesis that post-infarct activation of cardiac sympathetic nerves stimulates expression of TH, and to a lesser extent NET, but this is countered in the left ventricle by infarction-induced cytokines that suppress TH and NET content. Transgenic animals will be used to test the role of cardiac cytokines (Aim 1) and increased nerve activity (Aim 2) in the regulation of neurotransmission after infarction, and to assess the physiological impact on the heart. Sympathetic neuron cultures and a cell line will be used to identify mechanisms by which depolarization and NE stimulate NET expression (Aim 3), and to identify transcription factors that mediate cytokine suppression of noradrenergic genes (Aim 4). These studies will determine if cytokines and nerve activity cause the pathological changes in post-infarct cardiac neurons, and will identify mechanisms that mediate the regulation of TH and NET by cytokines and sympathetic activation. This work tests novel hypotheses that may explain the molecular basis for harmful alterations in the post-cardiac innervation, and lead to the development of novel therapeutics.
| Pinkham, Maximilian I; Loftus, Michael T; Amirapu, Satya et al. (2017) Renal denervation in male rats with heart failure improves ventricular sympathetic nerve innervation and function. Am J Physiol Regul Integr Comp Physiol 312:R368-R379 |
| Olivas, Antoinette; Gardner, Ryan T; Wang, Lianguo et al. (2016) Myocardial Infarction Causes Transient Cholinergic Transdifferentiation of Cardiac Sympathetic Nerves via gp130. J Neurosci 36:479-88 |
| Habecker, Beth A; Anderson, Mark E; Birren, Susan J et al. (2016) Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease. J Physiol 594:3853-75 |
| Gardner, Ryan T; Ripplinger, Crystal M; Myles, Rachel C et al. (2016) Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias. Circ Arrhythm Electrophysiol 9:e001359 |
| Ajijola, Olujimi A; Shivkumar, Kalyanam; Habecker, Beth A (2016) Natriuretic peptides and peripheral autonomic neurotransmission: back to the A, B, and C's. Cardiovasc Res 112:619-621 |
| Gardner, R T; Wang, L; Lang, B T et al. (2015) Targeting protein tyrosine phosphatase ? after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nat Commun 6:6235 |
| Melone, Mariarosa A B; Pellegrino, Michael J; Nolano, Maria et al. (2014) Unusual Stüve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy. Ann Clin Transl Neurol 1:926-32 |
| Pellegrino, Michael J; McCully, Belinda H; Habecker, Beth A (2014) Leptin stimulates sympathetic axon outgrowth. Neurosci Lett 566:1-5 |
| Emanueli, Costanza; Meloni, Marco; Hasan, Wohaib et al. (2014) The biology of neurotrophins: cardiovascular function. Handb Exp Pharmacol 220:309-28 |
| Wehrwein, Erica A; Novotny, Martin; Swain, Greg M et al. (2013) Regional changes in cardiac and stellate ganglion norepinephrine transporter in DOCA-salt hypertension. Auton Neurosci 179:99-107 |
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