Absence of gp130 in dopamine beta-hydroxylase-expressing neurons leads to autonomic imbalance and increased reperfusion arrhythmias.
ABSTRACT Inflammatory cytokines that act through glycoprotein (gp)130 are elevated in the heart after myocardial infarction and in heart failure. These cytokines are potent regulators of neurotransmitter and neuropeptide production in sympathetic neurons but are also important for the survival of cardiac myocytes after damage to the heart. To examine the effect of gp130 cytokines on cardiac nerves, we used gp130(DBH-Cre/lox) mice, which have a selective deletion of the gp130 cytokine receptor in neurons expressing dopamine beta-hydroxylase (DBH). Basal sympathetic parameters, including norepinephrine (NE) content, tyrosine hydroxylase expression, NE transporter expression, and sympathetic innervation density, appeared normal in gp130(DBH-Cre/lox) compared with wild-type mice. Likewise, basal cardiovascular parameters measured under isoflurane anesthesia were similar in both genotypes, including mean arterial pressure, left ventricular peak systolic pressure, dP/dt(max), and dP/dt(min). However, pharmacological interventions revealed an autonomic imbalance in gp130(DBH-Cre/lox) mice that was correlated with an increased incidence of premature ventricular complexes after reperfusion. Stimulation of NE release with tyramine and infusion of the beta-agonist dobutamine revealed blunted adrenergic transmission that correlated with decreased beta-receptor expression in gp130(DBH-Cre/lox) hearts. Due to the developmental expression of the DBH-Cre transgene in parasympathetic ganglia, gp130 was eliminated. Cholinergic transmission was impaired in gp130(DBH-Cre/lox) hearts due to decreased parasympathetic drive, but tyrosine hydroxylase immunohistochemistry in the brain stem revealed that catecholaminergic nuclei appeared grossly normal. Thus, the apparently normal basal parameters in gp130(DBH-Cre/lox) mice mask an autonomic imbalance that includes alterations in sympathetic and parasympathetic transmission.
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ABSTRACT: Obesity increases the risk of arrhythmias and sudden cardiac death, but the mechanisms are unknown. This study tested the hypothesis that obesity-induced cardiac sympathetic outgrowth and hyperinnervation promotes the development of arrhythmic events. Male Sprague Dawley rats (250-275g) fed a high fat diet (33%kcal/fat) diverged into obesity-resistant (OR) and obesity-prone (OP) groups, and were compared to rats fed normal chow (13% kcal/fat, CON). In vitro experiments showed that both OR and OP rats exhibited hyperinnervation of the heart and high sympathetic outgrowth compared to CON rats, even though OR rats are not obese. Despite the hyperinnervation and outgrowth, we showed that in vivo, OR rats were less susceptible to arrhythmic events after an intravenous epinephrine challenge compared to OP rats. On examining total and stimulus-evoked neurotransmitter levels in an ex-vivo system, we demonstrate that atrial acetylcholine content and release were attenuated in OP compared to OR and CON groups. OP rats also expressed elevated atrial NE content, while NE release was suppressed. These findings suggest that the consumption of a high fat diet, even in the absence of overt obesity, stimulates sympathetic outgrowth and hyperinnervation of the heart. However, normalized cardiac PNS control may protect the heart from arrhythmic events.AJP Heart and Circulatory Physiology 09/2013; · 4.01 Impact Factor
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ABSTRACT: Heart rate is controlled by stimulatory sympathetic and inhibitory parasympathetic nerves innervating the sino-atrial node and cardiac conduction system. Sympathetic release of norepinephrine (NE) and parasympathetic release of acetylcholine (ACh) are controlled by the central nervous system, and by pre-synaptic inhibition of transmitter release within the atria. An increase in cardiac sympathetic transmission relative to parasympathetic transmission is pathological as it can lead to disturbances in heart rhythm, catecholaminergic toxicity and development of arrhythmias or fibrillation. Mice lacking the p75 neurotrophin receptor (p75−/−) have elevated atrial NE but a low heart rate suggesting autonomic dysregulation. Similarly, mice whose sympathetic neurons lack the gp130 cytokine receptor (gp130 KO) have a normal heart rate but enhanced bradycardia after vagal nerve stimulation. What is unclear is whether cardiac autonomic disturbances in these animals reflect systemic alterations in nerve activity or whether localized defects in neurotransmitter stores or release are involved. To examine local stimulus-evoked release of neurotransmitters, we have developed a novel method for simultaneous quantification of both NE and ACh after ex vivo atrial field stimulation. Using HPLC with electrochemical detection for NE, and HPLC with mass spectrometry for ACh, we found that following field stimulation NE release was impaired in p75−/− atria while ACh content and release was elevated in gp130 KO atria. Thus, alterations in localized transmitter release from atrial explants are consistent with in vivo deficits in heart rate control, suggesting peripheral alterations in autonomic transmission in these mice.Neuroscience Letters 10/2012; 529(1):55–59. · 2.06 Impact Factor
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ABSTRACT: Development of cardiac sympathetic heterogeneity after myocardial infarction contributes to ventricular arrhythmias and sudden cardiac death. Regions of sympathetic hyperinnervation and denervation appear in the viable myocardium beyond the infarcted area. While elevated nerve growth factor (NGF) is implicated in sympathetic hyperinnervation, the mechanisms underlying denervation are unknown. Recent studies show that selective activation of the p75 neurotrophin receptor (P75(NTR)) in sympathetic neurons causes axon degeneration. We used mice that lack p75(NTR) to test the hypothesis that activation of p75(NTR) causes peri-infarct sympathetic denervation after cardiac ischemia-reperfusion. Wild type hearts exhibited sympathetic denervation adjacent to the infarct 24hours and 3days after ischemia-reperfusion, but no peri-infarct sympathetic denervation occurred in p75(NTR)-/- mice. Sympathetic hyperinnervation was found in the distal peri-infarct myocardium in both genotypes 3days after MI, and hyperinnervation was increased in the p75(NTR)-/- mice. By 7days after ischemia-reperfusion, cardiac sympathetic innervation density returned back to sham-operated levels in both genotypes, indicating that axonal pruning did not require p75(NTR). Prior studies revealed that proNGF is elevated in the damaged left ventricle after ischemia-reperfusion, as is mRNA encoding brain derived neurotrophic factor (BDNF). ProNGF and BDNF preferentially bind p75(NTR) rather than TrkA on sympathetic neurons. Immunohistochemistry using Bdnf-HA mice confirmed the presence of BDNF or proBDNF in the infarct after ischemia-reperfusion. Thus, at least two p75(NTR) ligands are elevated in the left ventricle after ischemia-reperfusion where they may stimulate p75(NTR)-dependent denervation of peri-infarct myocardium. In contrast, NGF-induced sympathetic hyperinnervation in the distal peri-infarct ventricle is attenuated by p75(NTR).Experimental Neurology 09/2013; · 4.62 Impact Factor