Sympathetic stimulation with norepinephrine may come at a cost.
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ABSTRACT:
SUBMITTER: Herat LY
PROVIDER: S-EPMC6404498 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
Publications
Sympathetic stimulation with norepinephrine may come at a cost.
Herat Lakshini Y LY Schlaich Markus P MP Matthews Vance B VB
Neural regeneration research 20190601 6
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Project description:BackgroundT-peak to T-end interval (Tp-e) is an independent marker of sudden cardiac death. Modulation of Tp-e by sympathetic nerve activation and circulating norepinephrine is not well understood. The purpose of this study was to characterize endocardial and epicardial dispersion of repolarization (DOR) and its effects on Tp-e with sympathetic activation.Methods and resultsIn Yorkshire pigs (n=13), a sternotomy was performed and the heart and bilateral stellate ganglia were exposed. A 56-electrode sock and 64-electrode basket catheter were placed around the epicardium and in the left ventricle (LV), respectively. Activation recovery interval, DOR, defined as variance in repolarization time, and Tp-e were assessed before and after left, right, and bilateral stellate ganglia stimulation and norepinephrine infusion. LV endocardial and epicardial activation recovery intervals significantly decreased, and LV endocardial and epicardial DOR increased during sympathetic nerve stimulation. There were no LV epicardial versus endocardial differences in activation recovery interval during sympathetic stimulation, and regional endocardial activation recovery interval patterns were similar to the epicardium. Tp-e prolonged during left (from 40.4±2.2 ms to 92.4±12.4 ms; P<0.01), right (from 47.7±2.6 ms to 80.7±11.5 ms; P<0.01), and bilateral (from 47.5±2.8 ms to 78.1±9.8 ms; P<0.01) stellate stimulation and strongly correlated with whole heart DOR during stimulation (P<0.001, R=0.86). Of note, norepinephrine infusion did not increase DOR or Tp-e.ConclusionsRegional patterns of LV endocardial sympathetic innervation are similar to that of LV epicardium. Tp-e correlated with whole heart DOR during sympathetic nerve activation. Circulating norepinephrine did not affect DOR or Tp-e.
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Project description:Familial dysautonomia (FD), a rare neurodevelopmental and neurodegenerative disorder affects the sympathetic and sensory nervous system. Although almost all patients harbor a mutation in ELP1, it remains unresolved exactly how function of sympathetic neurons (symNs) is affected; knowledge critical for understanding debilitating disease hallmarks, including cardiovascular instability or dysautonomic crises, that result from dysregulated sympathetic activity. Here, we employ the human pluripotent stem cell (hPSC) system to understand symN disease mechanisms and test candidate drugs. FD symNs are intrinsically hyperactive in vitro, in cardiomyocyte co-cultures, and in animal models. We report reduced norepinephrine transporter expression, decreased intracellular norepinephrine (NE), decreased NE re-uptake, and excessive extracellular NE in FD symNs. SymN hyperactivity is not a direct ELP1 mutation result, but may connect to NET via RAB proteins. We found that candidate drugs lowered hyperactivity independent of ELP1 modulation. Our findings may have implications for other symN disorders and may allow future drug testing and discovery.
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Project description:The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.
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Project description:The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis has been a topic of debate. Here, we identify sympathetic neuron-associated macrophages (SAMs) as a population of macrophages that mediate clearance of NE via expression of Slc6a2, an NE transporter, and monoamine oxidase A (MAOa), a degradation enzyme. Optogenetic activation of the SNS upregulates NE uptake by SAMs and shifts the SAM profile to a more pro-inflammatory state. NE uptake by SAMs is prevented by genetic depletion of Slc6a2 or inhibition of the transporter. We also found that obesity increases SAM content in the SNS. In two mouse models of obesity, genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis and leads to significant and sustained weight loss. We further show that this pathway is conserved as human sympathetic ganglia also contain SAMs and the analogous molecular machinery for NE clearance, thus constituting a potential target for obesity treatment.
2017-10-09 | GSE103847 | GEO
Project description:ObjectiveThis study aimed to address the status, role, and mechanism of sympathetic nerve infiltration in the progression of stomach adenocarcinoma (STAD).MethodsSympathetic nerve and its neurotransmitter NE, β-ARs, and associated signaling molecules in the STAD tissues and the adjacent tissues from 46 STAD patients were examined using immunostaining, HPLC, and western blotting. The effects and mechanisms of β2-AR activation on the proliferation, migration and invasion of AGS and SGC-7901 gastric cancer (GC) cell lines were examined using CCK-8, transwell, and western blotting assays. Correlations between genes and STAD survival were analyzed using bioinformatics.ResultsStriking sympathetic nerve infiltration, elevations of NGF, TrkA, GAP43, TH, S100, NE, β2-AR, YKL-40, syndecan-1, MMP9, CD206, and CD31 were observed in the STAD tissues compared to the adjacent tissues. Activation of β2-AR in the two GC cell lines significantly amplified the expressions of NGF, YKL-40, MMP9, syndecan-1, p-STAT3 and p-ERK, and increased GC cell proliferation, migration and invasion. Bioinformatic analyses revealed positive correlations of NGF, β2-AR, syndecan-1, and macrophage infiltration, respectively, with low survival of STAD, of β2-AR respectively with STAT3, ERK1/2 (MAPK1/3), YKL-40, MMP9, and syndecan-1, and of YKL-40 with MMP9.ConclusionSympathetic nerves significantly infiltrated into human STAD tissues as a result of high NGF and TrkA expressions; elevated NE led to overactivation of β2-AR-STAT3/ERK-YKL-40 signaling pathway, and finally caused cancer cell growth and invasion, M2 macrophage infiltration, angiogenesis, matrix degradation and STAD metastasis and progression.
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Project description:Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin-dependent protein kinase II-γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g-deficient mice exhibits attenuated imiquimod-induced psoriasis-like manifestations and skin inflammation. CaMK2γ regulates dermal γδT-cell interleukin-17 production in imiquimod-treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor β1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve-norepinephrine-γδT cell-adrenoceptor β1-nuclear factor-κB and -p38 axis activation. Application of alcaftadine, a small-molecule CaMK2γ inhibitor, relieves imiquimod-induced psoriasis-like manifestations in mice. This study reveals the mechanisms of sympathetic-nervous-system regulation of γδT-cell interleukin-17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.
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Project description:Cardiovascular risk rapidly increased following exposure to air pollution. Changes in human autonomic regulation have been implicated based on epidemiological associations between exposure estimates and indirect autonomic nervous system measurements. We conducted a mechanistic study to test the hypothesis that, in healthy older individuals, well-defined experimental exposure to ultrafine carbon particles (UFP) increases sympathetic nervous system activity and more so with added ozone (O3). Eighteen participants (age >50 years, 6 women) were exposed to filtered air (Air), UFP, and UFP + O3 combination for 3 hours during intermittent bicycle ergometer training in a randomized, crossover, double-blind fashion. Two hours following exposure, respiration, electrocardiogram, blood pressure, and muscle sympathetic nerve activity (MSNA) were recorded at supine rest, during deep breathing, and during a Valsalva manoeuvre. Catechols and inflammatory marker levels were measured in venous blood samples. Induced sputum was obtained 3.5 h after exposure. Combined exposure to UFP + O3 but not UFP alone, caused a significant increase in sputum neutrophils and circulating leucocytes. Norepinephrine was modestly increased while the ratio between plasma dihydroxyphenylglycol (DHPG) and norepinephrine levels, a marker for norepinephrine clearance, was reduced with UFP + O3. Resting MSNA was not different (47 ± 12 with Air, 47 ± 14 with UFP, and 45 ± 14 bursts/min with UFP + O3). Indices of parasympathetic heart rate control were unaffected by experimental air pollution. Our study suggests that combined exposure to modest UFP and O3 levels increases peripheral norepinephrine availability through decreased clearance rather than changes in central autonomic activity. Pulmonary inflammatory response may have perturbed pulmonary endothelial norepinephrine clearance.
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