The long term goal of the proposed research is to understand the molecular basis for the depletion of norepinephrine (NE) and loss of NE uptake in the peri-infarct sympathetic innervation following myocardial infarction (MI). Myocardial infarction can lead to ventricular arrhythmias and heart failure, and is a leading cause of mortality and morbidity in the United States. Changes in the cardiac innervation following Ml play a crucial role in the development of arrhythmias and heart failure, but the mechanisms that underlie the depletion of NE and loss of NE uptake in the peri-infarct innervation remain unknown. Several lines of evidence suggest a completely novel hypothesis that can account for these changes in the peri-infarct innervation. First, infarction is accompanied by the elevation of inflammatory cytokines, and interleukin-6 (IL-6) in particular. Sympathetic neurons have receptors for IL-6, and other cytokines in the IL-6 family suppress NE synthesis and reuptake in sympathetic neurons while inducing the production of peptides including vasoactive intestinal peptide (VIP). IL-6 shares common receptors and signaling pathways with these related cytokines. and our preliminary data indicate that IL-6 suppresses NE uptake and induces VIP in cultured sympathetic neurons. Therefore, we hypothesize that IL-6 released in the heart after infarction causes the depletion of neuronal NE and loss of NE uptake observed in the peri-infarct cardiac innervation. To test this hypothesis we will determine if: 1) IL-6 suppresses NE and NE synthetic enzymes in sympathetic neurons, 2) IL-6 suppresses NE uptake and the NE transporter in sympathetic neurons, 3) IL-6 suppresses neunopeptide Y and induces other neuropeptides in sympathetic neurons, and 4) suppression of inflammatony cytokines or the absence of IL-6 during and after infarction prevents the depletion of NE and loss of NE uptake in the peri-infarct cardiac innervation. A variety of molecular, biochemical, and histological approaches will be used to carry out these experiments both in vitro and in vivo. These studies will determine if IL-6 is a key player in the pathological changes in the cardiac innervation following infarction, and will identify the sites at which IL-6 regulates sympathetic function. This work tests a novel hypothesis that would provide a mechanistic explanation for the depletion of neuronal NE and NE uptake following infarction, and will provide the scientific basis for the development of new therapies These studies will also provide new and important information about the expression of vasoactive peptides in the heart following infarction. Similar changes in IL-6 and NE uptake occur during heart failure as well, indicating that these studies will have implications beyond the treatment of myocardial infarction.
| 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 |
| 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 |
| 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 |
| 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 |
Showing the most recent 10 out of 34 publications
