title: Human sympathetic nerve biology: parallel influences of stress and epigenetics in essential hypertension and panic disorder.
abstract: Patients with panic disorder provide a clinical model of stress. On a "good day," free from a panic attack, they show persistent stress-related changes in sympathetic nerve biology, including abnormal sympathetic nerve single-fiber firing ("salvos" of multiple firing within a cardiac cycle) and release of epinephrine as a cotransmitter. The coreleased epinephrine perhaps originates from in situ synthesis by phenylethanolamine N-methyltransferase (PNMT). In searching for biological evidence that essential hypertension is caused by mental stress--a disputed proposition--we note parallels with panic disorder, which provides an explicit clinical model of stress: (1) There is clinical comorbidity; panic disorder prevalence is increased threefold in essential hypertension. (2) For both, epinephrine cotransmission is present in sympathetic nerves. (3) In panic disorder and essential hypertension, but not in health, single-fiber sympathetic nerve firing salvos occur. (4) Tissue nerve growth factor is increased in both conditions (nerve growth factor is a stress reactant). (5) There is induction of PNMT in sympathetic nerves. Essential hypertension exhibits a further manifestation of mental stress: there is activation of noradrenergic brain stem neurons projecting to the hypothalamus and amygdala. These pathophysiological findings strongly support the view that chronic mental stress is important in the pathogenesis of essential hypertension. A hypothesis now under test is whether in both disorders, under prevailing conditions of ongoing stress, PNMT induced in sympathetic nerves acts as a DNA methylase, causing the norepinephrine transporter (NET) gene silencing that is present in both conditions. PNMT can have an intranuclear distribution, binding to DNA. We have demonstrated that the reduced neuronal noradrenaline reuptake present in both disorders does have an epigenetic mechanism, with demonstrable reduction in the abundance of the transporter protein, the NET gene silencing being associated with DNA binding by the methylation-related inhibitory transcription factor MeCP2.
authors.affiliation: Baker Heart Research Institute, Melbourne, Australia. murray.esler@baker.edu.au
authors.forename: Murray
authors.initials: M
authors.lastname: Esler
authors.forename: Nina
authors.initials: N
authors.lastname: Eikelis
authors.forename: Markus
authors.initials: M
authors.lastname: Schlaich
authors.forename: Gavin
authors.initials: G
authors.lastname: Lambert
authors.forename: Marlies
authors.initials: M
authors.lastname: Alvarenga
authors.forename: David
authors.initials: D
authors.lastname: Kaye
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.forename: David
authors.initials: D
authors.lastname: Barton
authors.forename: Ciaran
authors.initials: C
authors.lastname: Pier
authors.forename: Celia
authors.initials: C
authors.lastname: Brenchley
authors.forename: Tye
authors.initials: T
authors.lastname: Dawood
authors.forename: Garry
authors.initials: G
authors.lastname: Jennings
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lambert
mesh_terms: D000200:Action Potentials / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004837:Epinephrine / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D016584:Panic Disorder / Q000209:etiology / Q000503:physiopathology*; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000033:anatomy & histology / Q000502:physiology* / Q000503:physiopathology*
chemical_list: D015415:Biomarkers; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D050484:Norepinephrine Plasma Membrane Transport Proteins; D020932:Nerve Growth Factor; D010625:Phenylethanolamine N-Methyltransferase; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine