Cardiac ischemia-reperfusion regulates sympathetic neuropeptide expression through gp130-dependent and independent mechanisms
Introduction
The autonomic nervous system regulates cardiac function by balancing the actions of sympathetic and parasympathetic inputs to the heart. Sympathetic neurons from the stellate ganglia stimulate heart rate, cardiac conduction, and the force of contraction through the release of norepinephrine (NE) and activation of adrenergic receptors. Conversely, parasympathetic neurons of the cardiac ganglia inhibit heart rate through the release acetylcholine (ACh) and activation of muscarinic ACh receptors. Autonomic imbalance, characterized by increased sympathetic and decreased parasympathetic activity, contributes to many life threatening cardiovascular pathologies (Esler, 1992, La Rovere et al., 2001, Lopez-Sendon et al., 2004, Schwartz, 1998). Cardiac parasympathetic transmission is usually depressed after myocardial infarction (MI), and this loss is a powerful predictor of susceptibility to arrhythmia and death (La Rovere et al., 1998, Nolan et al., 1998). Cardiac parasympathetic transmission is inhibited by the release of neuropeptide Y (NPY)(Herring et al., 2008, Pirola and Potter, 1990, Smith-White et al., 2003) and galanin (GAL) (Smith-White et al., 2003, Ulman et al., 1992), from cardiac sympathetic neurons. Increased activation of sympathetic nerves after myocardial infarction (Graham et al., 2002, Karlsberg et al., 1979), and the corresponding increase in peptide release may contribute to the loss of parasympathetic transmission.
Neuropeptide expression is altered in cardiac sympathetic neurons following myocardial infarction, and these changes are similar to neuropeptide changes after axotomy. For example, vasoactive intestinal peptide (VIP)(Roudenok et al., 2001) and Galanin (GAL) (Ewert et al., 2008, Habecker et al., 2005) increase after myocardial infarction in cardiac sympathetic neurons. Axotomy stimulates expression of VIP, substance P (SubP), pituitary adenylate cyclase activating peptides (PACAP), and GAL in the superior cervical ganglion (Bergner et al., 2000, Boeshore et al., 2004, Hyatt-Sachs et al., 1993, Klimaschewski et al., 1994, Rao et al., 1993, Schreiber et al., 1994) by activation of the gp130 cytokine receptor (Habecker et al., 2009, Heinrich et al., 1998). A number of gp130 cytokines are elevated in the heart following myocardial infarction, including Interleukin-6 (IL-6), Leukemia Inhibitory Factor (LIF), and Cardiotrophin-1 (CT-1)(Aoyama et al., 2000, Frangogiannis et al., 2002, Gwechenberger et al., 1999), where they might stimulate neuropeptide expression in cardiac sympathetic nerves.
Cytokines that activate gp130 are important survival factors for cardiac myocytes (Brar et al., 2001, Hirota et al., 1999, Yoshida et al., 1996, Zou et al., 2003), so to determine the effect of cytokines on neuropeptide expression in cardiac neurons, we used gp130DBH-Cre/lox mice that have a selective deletion of gp130 in neurons expressing dopamine beta hydroxylase (DBH) (Stanke et al., 2006). Injury-induced inflammatory cytokines do not activate STAT3 in sympathetic neurons from these mice, confirming the absence of gp310 signaling (Habecker et al., 2009, Hyatt Sachs et al., 2010). Therefore, we used these mice to ask if cytokine activation of gp130 was critical for regulation of neuropeptide expression in cardiac sympathetic nerves after myocardial infarction.
Section snippets
Ethical approval
All procedures were approved by the OHSU Institutional Animal Care and Use Committee and comply with the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH publication No. 85-23, revised 1996).
Materials
Antibodies were obtained as follows: rabbit anti-GAL as well as rabbit and sheep anti-TH were from Chemicon/Millipore (Temecula, CA), goat anti-PACAP (C19; raised against C-terminus of human PACAP and presumed to identify PACAP27&38) was from
Results
Basal expression of NPY, VIP, and GAL mRNA in the stellate ganglion of unoperated control gp130 KO mice did not differ significantly from wild type (WT) levels (Fig. 1), but PACAP mRNA was significantly lower in stellates from unoperated KO mice compared to WT mice (Fig. 1). Several changes occurred in peptide mRNA expression after myocardial infarction. NPY mRNA decreased significantly in both genotypes three and seven days (Fig. 2) after MI. GAL mRNA did not increase in either genotype after
Discussion
Cardiac sympathetic neurons in most species produce NPY, which has well-characterized effects on cardiac parasympathetic transmission (Herring et al., 2008) in addition to direct effects on the heart (Allen et al., 1983). NPY expression can be stimulated by nerve activity (Rao et al., 1992) and suppressed by inflammatory cytokines (Lewis et al., 1994).
Plasma NPY is increased 3Ā days after acute myocardial infarction in humans (Omland et al., 1994). This is thought to be due to enhanced release,
Acknowledgement
This work was supported by HL068231 (BAH).
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