title: The neuronal noradrenaline transporter, anxiety and cardiovascular disease.
abstract: 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.
authors.affiliation: Baker Heart Research Institute, Melbourne, Australia.
authors.forename: Murray
authors.initials: M
authors.lastname: Esler
authors.forename: Marlies
authors.initials: M
authors.lastname: Alvarenga
authors.forename: Ciaran
authors.initials: C
authors.lastname: Pier
authors.forename: Jeff
authors.initials: J
authors.lastname: Richards
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: David
authors.initials: D
authors.lastname: Barton
authors.forename: Deepak
authors.initials: D
authors.lastname: Haikerwal
authors.forename: David
authors.initials: D
authors.lastname: Kaye
authors.forename: Markus
authors.initials: M
authors.lastname: Schlaich
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: Garry
authors.initials: G
authors.lastname: Jennings
authors.forename: Flora
authors.initials: F
authors.lastname: Socratous
authors.forename: Gavin
authors.initials: G
authors.lastname: Lambert
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019175:DNA Methylation; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D009638:Norepinephrine