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Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood.

ABSTRACT: Adverse childhood experiences (ACEs) are psychosocial stressors that occur during sensitive developmental windows and are associated with increased lifetime cardiovascular disease (CVD) risk in a dose-dependent manner. Vascular endothelial dysfunction is a pathophysiological mechanism that promotes hypertension and CVD and may be a mechanism by which ACEs contribute to lifetime CVD risk. We examined whether exposure to ACEs is associated with reduced vascular endothelial function (VEF) in otherwise healthy, young adult women (20.7 ± 3 yr) with (ACE⁺) versus without (ACE^-) ACEs, explored whether differences in circulating sirtuin 1 (SIRT1) or systemic oxidative stress could explain ACEs-related differences in VEF, and examined the ability of a pilot, 8-wk exercise intervention to augment VEF and SIRT1 or reduce oxidized LDL cholesterol (oxLDL) in ACE⁺ young adult women. Forty-two otherwise healthy young adults completed this study. Prior to the intervention, VEF (P = 0.002) and SIRT1 (P = 0.004) were lower in the ACE⁺ than ACE^- group, but oxLDL concentrations were not different (P = 0.77). There were also significant relationships (P ≤ 0.04) among flow-mediated dilation (FMD), SIRT1, and oxLDL in the ACE⁺, but not ACE^- group. Adjusting for circulating SIRT1 and oxLDL reduced the differences in FMD observed between groups (P = 0.10), but only SIRT1 was a significant adjuster of the means (P < 0.05). Finally, the exercise intervention employed was unable to enhance VEF or SIRT1 in the ACE⁺ exercise group. Our data suggest that ACEs likely increase susceptibility to hypertension and CVD by causing endothelial dysfunction, perhaps through a SIRT1 pathway-related mechanism.NEW & NOTEWORTHY Our study provides novel evidence that young adult women with moderate-to-severe adverse childhood experience (ACE) exposure present impaired endothelial function and lower circulating sirtuin 1 (SIRT1) concentrations than age-matched controls. However, an 8-wk exercise intervention was unable to augment endothelial function or SIRT1 concentrations in a subset of those with ACEs. Our data suggest that ACEs-related impairments in endothelial function may be secondary to decreased NO bioavailability via SIRT1 and/or oxidative stress-related mechanisms.

SUBMITTER: Jenkins NDM

PROVIDER: S-EPMC8461842 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood.

Jenkins Nathaniel D M NDM Rogers Emily M EM Banks Nile F NF Tomko Patrick M PM Sciarrillo Christina M CM Emerson Sam R SR Taylor Ashlee A Teague T Kent TK

American journal of physiology. Heart and circulatory physiology 20210730 3

Adverse childhood experiences (ACEs) are psychosocial stressors that occur during sensitive developmental windows and are associated with increased lifetime cardiovascular disease (CVD) risk in a dose-dependent manner. Vascular endothelial dysfunction is a pathophysiological mechanism that promotes hypertension and CVD and may be a mechanism by which ACEs contribute to lifetime CVD risk. We examined whether exposure to ACEs is associated with reduced vascular endothelial function (VEF) in otherw ...[more]

PMID: 34328346

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Project description:ImportanceEmerging research suggests that factors associated with the built environment, including artificial light, air pollution, and noise, may adversely affect children's mental health, while living near green space may reduce stress. Little is known about the combined roles of these factors on children's stress.ObjectiveTo investigate associations between components of the built environment with personal and home characteristics in a large cohort of children who were assessed for perceived stress.Design, setting, and participantsIn this cohort study, a total of 2290 Southern California Children's Health Study participants residing in 8 densely populated urban communities responded to detailed questionnaires. Exposures of artificial light at night (ALAN) derived from satellite observations, near-roadway air pollution (NRP) determined from a dispersion model, noise estimated from the US Traffic Noise Model, and green space from satellite observations of the enhanced vegetation index were linked to each participant's geocoded residence.Main outcomes and measuresChildren's stress was assessed at ages 13 to 14 years and 15 to 16 years using the 4-item Perceived Stress Scale (PSS-4), scaled from 0 to 16, with higher scores indicating greater perceived stress. Measurements were conducted in 2010 and 2012, and data were analyzed from February 6 to August 24, 2019. Multivariate mixed-effects models were used to examine multiple exposures; modification and mediation analyses were also conducted.ResultsAmong the 2290 children in this study, 1149 were girls (50%); mean (SD) age was 13.5 (0.6) years. Girls had significantly higher perceived stress measured by PSS-4 (mean [SD] score, 5.7 [3.4]) than boys (4.9 [3.2]). With increasing age (from 13.5 [0.6] to 15.3 [0.6] years), the mean PSS-4 score rose from 5.6 (3.3) to 6.0 (3.4) in girls but decreased for boys from 5.0 (3.2) to 4.7 (3.1). Multivariate mixed-effects models examining multiple exposures indicated that exposure to secondhand smoke in the home was associated with a 0.85 (95% CI, 0.46-1.24) increase in the PSS-4 score. Of the factors related to the physical environment, an interquartile range (IQR) increase in ALAN was associated with a 0.57 (95% CI, 0.05-1.09) unit increase in the PSS-4 score together with a 0.16 score increase per IQR increase of near-roadway air pollution (95% CI, 0.02-0.30) and a -0.24 score decrease per IQR increase of the enhanced vegetation index (95% CI, -0.45 to -0.04). Income modified the ALAN effect size estimate; participants in households earning less than $48 000 per year had significantly greater stress per IQR increase in ALAN. Sleep duration partially mediated the associations between stress and both enhanced vegetation index (17%) and ALAN (18%).Conclusions and relevanceIn this cohort study, children's exposure to smoke at home in addition to residential exposure to ALAN and near-roadway air pollution were associated with increased perceived stress among young adolescent children. These associations appeared to be partially mitigated by more residential green space. The findings may support the promotion of increased residential green spaces to reduce pollution associated with the built environment, with possible mental health benefits for children.

Project description:Vitamin B12 (cobalamin) is a key determinant of S-adenosyl methionine (SAM)-dependent epigenomic cellular regulations related to methylation/acetylation and its deficiency produces neurodegenerative disorders by elusive mechanisms. Sirtuin 1 deacetylase (SIRT1) triggers cell response to nutritional stress through endoplasmic reticulum (ER) stress. Recently, we have established a N1E115 dopaminergic cell model by stable expression of a transcobalamin-oleosin chimera (TO), which impairs cellular availability of vitamin B12, decreases methionine synthase activity and SAM level, and reduces cell proliferation. In contrast, oleosin-transcobalamin chimera (OT) does not modify the phenotype of transfected cells. Presently, the impaired cellular availability of vitamin B12 in TO cells activated irreversible ER stress pathways, with increased P-eIF-2α, P-PERK, P-IRE1α, ATF6, ATF4, decreased chaperon proteins and increased pro-apoptotic markers, CHOP and cleaved caspase 3, through reduced SIRT1 expression and consequently greater acetylation of heat-shock factor protein 1 (HSF1). Adding either B12, SIRT1, or HSF1 activators as well as overexpressing SIRT1 or HSF1 dramatically reduced the activation of ER stress pathways in TO cells. Conversely, impairing SIRT1 and HSF1 by siRNA, expressing a dominant negative form of HSF1, or adding a SIRT1 inhibitor led to B12-dependent ER stress in OT cells. Addition of B12 abolished the activation of stress transducers and apoptosis, and increased the expression of protein chaperons in OT cells subjected to thapsigargin, a strong ER stress stimulator. AdoX, an inhibitor of methyltransferase activities, produced similar effects than decreased B12 availability on SIRT1 and ER stress by a mechanism related to increased expression of hypermethylated in cancer 1 (HIC1). Taken together, these data show that cellular vitamin B12 has a strong modulating influence on ER stress in N1E115 dopaminergic cells. The impaired cellular availability in vitamin B12 induces irreversible ER stress by greater acetylation of HSF1 through decreased SIRT1 expression, whereas adding vitamin B12 produces protective effects in cells subjected to ER stress stimulation.

Dataset Information

Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood.

Publications

Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood.

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