Regulation of Sympathetic Function by Infarction

Oregon Health & Science University, Portland OR

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): 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.