The neuronal noradrenaline transporter, anxiety and cardiovascular disease

Baker Heart Research Institute, Melbourne, Australia.
Journal of Psychopharmacology (Impact Factor: 3.59). 08/2006; 20(4 Suppl):60-6. DOI: 10.1177/1359786806066055
Source: PubMed


Panic disorder can serve as a clinical model for testing whether mental stress can cause heart disease. Potential neural mechanisms of cardiac risk are the sympathetic activation during panic attacks, continuing release of adrenaline as a co-transmitter in the cardiac sympathetic nerves, and impairment of noradrenaline neuronal reuptake, augmenting sympathetic neural respnses. The phenotype of impaired neuronal reuptake of noradrenaline: an epigenetic mechanism? We suspect that this phenotype, in sensitizing people to heart symptom development, is a cause of panic disorder, and by magnifying the sympathetic neural signal in the heart, underlies increased cardiac risk. No loss of function mutations of the coding region of the norepinephrine transporter (NET) are evident, but we do detect hypermethylation of CpG islands in the NET gene promoter region. Chromatin immunoprecipitation methodology demonstrates binding of the inhibitory transcription factor, MeCP2, to promoter region DNA in panic disorder patients. Cardiovascular illnesses co-morbid with panic disorder. Panic disorder commonly coexists with essential hypertension and the postural tachycardia syndrome. In both of these cardiovascular disorders the impaired neuronal noradrenaline reuptake phenotype is also present and, as with panic disorder, is associated with NET gene promoter region DNA hypermethylation. An epigenetic 'co-morbidity' perhaps underlies the clinical concordance. Brain neurotransmitters. Using internal jugular venous sampling, in the absence of a panic attack we find normal norepinephrine turnover, but based on measurements of the overflow of the serotonin metabolite, 5HIAA, a marked increase (six to sevenfold) in brain serotonin turnover in patients with panic disorder. This appears to represent the underlying neurotransmitter substrate for the disorder. Whether this brain serotonergic activation is a prime mover, or consequential on other primary causes of panic disorder, including cardiac sensitization by faulty neuronal noradrenaline reuptake leading to cardiac symptoms and the enhanced vigilance which accompanies them, is unclear at present.

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    • "Impairment of NET has been associated with diverse neurological diseases like Alzheimer and Parkinson; psychiatric disorders like depression and attention-deficit hyperactivity disorder; as well as cardiovascular diseases like congestive heart failure, blood pressure elevation, and postural tachycardia syndrome (B€ onish & Br€ uss, 2006; Esler et al., 2006; Kristensen et al., 2011; Liang, 2007; Schroeder & Jordan, 2012; Shannon et al., 2000; Tellioglu & Robertson, 2001; Whiskey & Taylor, 2013). Whether NET impairment is involved in the genesis and/or maintenance of these pathophysiological conditions remains to be further elucidated. "
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    ABSTRACT: Neuronal norepinephrine (NE) uptake is a crucial step in noradrenergic neurotransmission that regulates NE concentration in the synaptic cleft. It is a key mechanism mediated by the NE transporter (NET) which takes the neurotransmitter into the presynaptic neuron terminal or the adrenal medulla chromaffin cell. The activity of NET is short and long terms modulated by phosphorylation mediated by protein kinases A, C, and G and calcium-calmodulin-dependent protein kinase, whereas the transporter availability at the cell surface is regulated by glycosylation. Several neuropeptides like angiotensins II, III, and 1-7, bradykinin, natriuretic peptides, as well as endothelins (ETs) regulate a wide variety of biological effects, including noradrenergic transmission and in particular neuronal NE uptake. Diverse reports, including studies from our laboratory, show that ETs differentially modulate the activity and expression of NET not only in normal conditions but also in diverse cardiovascular diseases such as congestive heart failure and hypertension. Current literature supports a key role for the interaction between ETs and NE in maintaining neurotransmission homeostasis and further suggests that this interaction may represent a potential therapeutic target for various diseases, particularly hypertension. © 2015 Elsevier Inc. All rights reserved.
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    • "Previous work from our group has noted the possible importance of epigenetic mechanisms in NET regulation. While an early report suggested that hypermethylation of the NET gene (SLC6a2) may lead to transcriptional repression of SLC6a2 (Esler et al., 2006), recent reports using more specific and robust methodology have found no evidence of methylation of the promoter of the NET gene (Bayles et al., 2013). Although methyl CpG binding protein (MeCP2) induced transcriptional repression of genes was originally proposed to be dependent on DNA methylation, recent studies, including our own, have established that this is not always the case (Bayles et al., 2010, 2012). "
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    ABSTRACT: Orthostatic intolerance is the inability to tolerate the upright posture and is relieved by recumbence. It most commonly affects young women and has a major impact on quality of life and psychosocial well-being. Several forms of orthostatic intolerance have been described. The most common one is the recurrent vasovagal syncope (VVS) phenotype which presents as a transient and abrupt loss of consciousness and postural tone that is followed by rapid recovery. Another common type of orthostatic intolerance is the postural orthostatic tachycardia syndrome (POTS) which is characterized by an excessive rise in heart rate upon standing and is associated with symptoms of presyncope such as light-headedness, fatigue, palpitations, and nausea. Maintenance of arterial pressure under condition of reduced central blood volume during the orthostasis is accomplished in large part through sympathetic efferent nerve traffic to the peripheral vasculature. Therefore sympathetic nervous system (SNS) dysfunction is high on the list of possible contributors to the pathophysiology of orthostatic intolerance. Investigations into the role of the SNS in orthostatic intolerance have yielded mixed results. This review outlines the current knowledge of the function of the SNS in both VVS and POTS.
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    • "The majority (12) of the studies included in the literature considered epigenetic modification in the etiology of suicide [14-25]. Five studies considered epigenetic factors and mood disorders (all five were concerned with depression) [12,26-29], and the remaining four studies considered epigenetic factors in the etiology of anxiety disorders (three considered PTSD and one considered panic disorder) [13,30-32]. "
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    ABSTRACT: Epigenetic modifications are those reversible, mitotically heritable alterations in genomic expression that occur independent of changes in gene sequence. Epigenetic studies have the potential to improve our understanding of the etiology of mood and anxiety disorders and suicide by bridging the gap in knowledge between the exogenous environmental exposures and pathophysiology that produce common mood and anxiety disorders and suicide. We systematically reviewed the English-language peer-reviewed literature about epigenetic regulation in these disorders between 2001-2011, summarizing and synthesizing this literature with respect to directions for future work. Twenty-one articles met our inclusion criteria. Twelve studies were concerned with epigenetic changes among suicide completers; other studies considered epigenetic regulation in depression, post-traumatic stress disorder, and panic disorder. Several studies focused on epigenetic regulation of amine, glucocorticoid, and serotonin metabolism in the production of common mood and anxiety disorders and suicide. The literature is nascent and has yet to reach consensus about the roles of particular epigenetic modifications in the etiology of these outcomes. Future studies require larger sample sizes and measurements of environmental exposures antecedent to epigenetic modification. Further work is also needed to clarify the link between epigenetic modifications in the brain and peripheral tissues and to establish 'gold standard' epigenetic assays.
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