Elsevier

Neuropeptides

Volume 45, Issue 1, February 2011, Pages 33-42
Neuropeptides

Cardiac ischemia-reperfusion regulates sympathetic neuropeptide expression through gp130-dependent and independent mechanisms

https://doi.org/10.1016/j.npep.2010.10.002Get rights and content

Abstract

Cardiac function is regulated by a balance of sympathetic and parasympathetic transmission. Neuropeptide Y (NPY) and galanin (GAL) released from cardiac sympathetic neurons inhibits parasympathetic transmission in the heart. Sympathetic peptides may contribute to autonomic imbalance, which is characterized by increased sympathetic and decreased parasympathetic transmission and contributes to life threatening cardiovascular pathologies. Several gp130 cytokines are increased in the heart after myocardial infarction (MI), and these cytokines stimulate neuropeptide expression in sympathetic neurons. We used mice whose sympathetic neurons lack the gp130 receptor (gp130DBH-Cre/lox mice) to ask if cytokine activation of gp130 regulated neuropeptide expression in cardiac sympathetic nerves after MI. Myocardial infarction decreased NPY mRNA through a gp130 independent mechanism and increased VIP and PACAP mRNA via gp130, while GAL mRNA was unchanged. Immunohistochemistry revealed a gp130-dependent increase in PACAP38 in cells of the stellate ganglion after MI, and PACAP was detected in pre-ganglionic fibers of all genotypes and surgical groups. VIP was identified in a few sympathetic nerve fibers in all genotypes and surgical groups. GAL and PACAP38 were not detected in sham hearts, but peptide immunoreactivity was high in the infarct three days after MI. Surprisingly, peptides were abundant in cells that co-labeled with macrophage markers F4/80 and MAC2, but were not detected in sympathetic axons. PACAP protects cardiac myocytes from apoptosis, and GAL stimulates axon regeneration in addition to inhibiting parasympathetic transmission. Thus, these peptides may play an important role in cardiac and neuronal remodeling after ischemia-reperfusion.

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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