Myocardial infarction alters sympathetic transmission in the heart, and sympathetic dysfunction is a major contributor to post-infarct ventricular arrhythmia and sudden cardiac death, which kill ~300,000/year in the U.S. The long term goal of the proposed research is to understand the molecular basis for altered sympathetic transmission following myocardial infarction. Infarction triggers two types of plasticity in cardiac sympathetic neurons. First are key neurotransmitter and neuropeptide changes, as extracellular norepinephrine (NE) increases together with neuronal expression of the peptides galanin and PACAP (pituitary adenylate cyclase- activating polypeptides). Second, axons degenerate in the viable peri-infarct myocardium soon after the initial injury and then re-grow heterogeneously leading to regional hyperinnervation. This proposal will test the hypothesis that infarction-induced neurotrophins are critical for the neurochemical and axonal plasticity seen in cardiac sympathetic neurons. The neurotrophins Nerve Growth Factor (NGF) and Brain Derived-Neurotrophic Factor (BDNF) are elevated in heart following infarction. Neurotrophins exert their effects on sympathetic neurons through two receptors, the TrkA tyrosine kinase receptor and the p75 receptor. Our preliminary data suggest that BDNF activation of p75 stimulates axon degeneration, while NGF activation of TrkA leads to axon outgrowth and increased neuropeptide expression in cardiac sympathetic neurons. The recent development of TrkAF592A mice offers a new opportunity to test the role of TrkA function in adult animals that have an intact sympathetic nervous system. Therefore, we will use genetic models to manipulate neurotrophin signaling in vivo and dissect the contributions of p75 and TrkA in post-infarct sympathetic dysregulation, including: 1) denervation, 2) hyper-innervation, 3) neuropeptide production, 4) NE synthesis and turnover, and 5) susceptibility to arrhythmias and control of cardiac function. To complement the whole animal studies we will carry out additional experiments in cultured cardiac sympathetic neurons to identify specific intracellular signaling pathways critical for control of axon size, neuropeptide synthesis, or neurotransmitter production. This research plan will advance our understanding of the molecular basis for pathological changes in the cardiac sympathetic innervation after infarction, and may facilitate targeted development of novel therapeutics.

Public Health Relevance

Myocardial infarction alters sympathetic transmission in the heart, and sympathetic dysfunction is a major contributor to post-infarct ventricular arrhythmia and sudden cardiac death, which are leading causes of death in the U.S. These studies will identify key factors regulating the pathological changes in sympathetic transmission after infarction, and may lead to the development of new therapeutic strategies in the treatment of myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093056-05
Application #
8463590
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (03))
Program Officer
Lathrop, David A
Project Start
2009-07-15
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$358,662
Indirect Cost
$123,042
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Li, Bingbing X; Gardner, Ryan; Xue, Changhui et al. (2016) Systemic Inhibition of CREB is Well-tolerated in vivo. Sci Rep 6:34513
Courter, Lauren A; Shaffo, Frances C; Ghogha, Atefeh et al. (2016) BMP7-induced dendritic growth in sympathetic neurons requires p75(NTR) signaling. Dev Neurobiol 76:1003-13
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, Ryan T; Ripplinger, Crystal M; Myles, Rachel C et al. (2016) Molecular Mechanisms of Sympathetic Remodeling and Arrhythmias. Circ Arrhythm Electrophysiol 9:e001359
Johnsen, Dustin; Olivas, Antoinette; Lang, Bradley et al. (2016) Disrupting protein tyrosine phosphatase σ does not prevent sympathetic axonal dieback following myocardial infarction. Exp Neurol 276:1-4
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, R T; Wang, L; Lang, B T et al. (2015) Targeting protein tyrosine phosphatase ýý after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias. Nat Commun 6:6235
Jones, Casey M; Baker-Groberg, Sandra M; Cianchetti, Flor A et al. (2014) Measurement science in the circulatory system. Cell Mol Bioeng 7:1-14
Pellegrino, Michael J; Habecker, Beth A (2013) STAT3 integrates cytokine and neurotrophin signals to promote sympathetic axon regeneration. Mol Cell Neurosci 56:272-82
Gardner, Ryan T; Habecker, Beth A (2013) Infarct-derived chondroitin sulfate proteoglycans prevent sympathetic reinnervation after cardiac ischemia-reperfusion injury. J Neurosci 33:7175-83

Showing the most recent 10 out of 17 publications