Abstract 57: Histone Deacetylase Inhibition Attenuates Early Life Stress-Induced Endothelial Dysfunction

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Dao H Ho ◽  
Jennifer S Pollock
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Histone Deacetylase ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Trichostatin A ◽  
Early Life Stress ◽  
Intercellular Adhesion Molecule ◽  
Pressure Independent

Epidemiological studies show that early life stress (ELS) is linked to cardiovascular disease in adulthood. We used a model of maternal separation with early weaning (MSEW) to study the mechanisms of ELS-mediated adult vascular dysfunction in male C57BL/6J mice. MSEW litters were subjected to maternal separation 4h/day (postnatal day (PD) 2 to 5) and 8h/day (PD6 to 16), and weaned at PD17. Control (CON) litters were undisturbed until weaning at PD21. All subsequent experiments were performed in adult mice (12 weeks old). We hypothesized that MSEW increases vascular inflammation and endothelial dysfunction in male mice. Systolic blood pressure (tail-cuff) of MSEW mice was not different from CON mice (109.3 + 10.9 vs 116.7 + 20.8 mmHg, respectively). Circulating soluble intercellular adhesion molecule (CON: 333.5 + 19.4 vs MSEW: 406.2 + 23.1 ng/ml; p = 0.03) and macrophage colony stimulating factor (CON: 737.4 + 19.6 vs MSEW: 945.3 + 65.4 pg/ml; p = 0.01) were elevated by MSEW. Also, aortic adventitial macrophage infiltration was increased in mice exposed to MSEW (F4/80 immunostaining; CON: 2.8 + 2.3 vs MSEW: 7.0 + 2.2 cells/mm 2 ; p = 0.05). We performed wire myography on thoracic aortae to determine vasorelaxation with cumulative concentration-response curve to acetylcholine (ACh; 1 X 10 -9 M to 3 X 10 -5 M) and sodium nitroprusside (SNP; 1 X 10 -10 M to 3 X 10 -5 M). MSEW induced blunted ACh-mediated vasorelaxation (MSEW: 67.6 + 5.8 vs CON: 89.9 + 2.7 % of phenylephrine constriction (% of PE), p = 0.01), while SNP-induced vasorelaxation was similar in CON and MSEW mice. We further hypothesized that MSEW-induced endothelial dysfunction is mediated via increased histone deacetylase (HDAC) expression. Real-time quantitative PCR revealed upregulation of HDAC 1, 6 and 9 in aortae of MSEW mice (1.28 + 0.12, 1.28 + 0.18 and 1.65 + 0.05 fold change from CON, respectively, p < 0.05). Pretreatment with trichostatin A (TSA), an HDAC inhibitor, normalized ACh-induced vasorelaxation in aortae of MSEW mice (MSEW: 67.6 + 5.8 vs MSEW + TSA: 88.44 + 3.2 % of PE, p = 0.02), while not affecting ACh-induced vasorelaxation in aortae from CON mice (CON: 89.9 + 2.7 vs CON + TSA: 90.3 + 4.5 % of PE). We conclude that ELS induces blood pressure-independent endothelial dysfunction through an HDAC-mediated pathway.

Abstract 335: Vascular Histone Deacetylase Mediates Early Life Stress-Induced Endothelial Dysfunction

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Dao H Ho ◽  
Jennifer S Pollock
Keyword(s):  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Protein Expression ◽  
Histone Deacetylase ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Chromatin Modification ◽  
Early Life Stress ◽  
Mrna Levels

Chromatin remodeling is an important factor in the etiology of vascular pathologies. Also, early life stress (ELS) is linked to increased risk of vascular disease in adults. We used maternal separation with early weaning (MSEW) to study mechanisms of ELS-mediated adult vascular dysfunction in male C57BL/6J mice. Litters were subjected to maternal separation 4h/day (postnatal day (PD) 2-5) and 8h/day (PD6-16), and weaned at PD17. Control (CON) litters were undisturbed until weaning at PD21. Subsequent experiments were performed at 12 weeks old. MSEW blunted aortic ACh-mediated vasorelaxation (MSEW: 68% vs CON: 90%, p=0.01), while SNP-induced vasorelaxation was similar in CON and MSEW aortae. Apocynin (300 μM) and superoxide dismutase (100 U/mL) normalized MSEW-induced endothelial dysfunction. We hypothesize that ELS induces aortic endothelial dysfunction by increasing NADPH oxidase expression and/or decreasing nitric oxide synthase 3 (NOS3) expression. Aortic protein expression of NADPH oxidase subunit p67 was elevated in MSEW mice (45% increase from CON, n=11, p=0.02). NOS3 protein expression and NOS3 serine 1177 phosphorylation was not different between groups, indicating that NOS3 activation by phosphorylation does not contribute to ELS-induced endothelial dysfunction. We further hypothesize that chromatin modification mediates ELS-induced endothelial dysfunction. Aortic mRNA expressions of 84 chromatin modification enzymes (methyltransferases, demethylases, acetyltransferases, deacetylases) were assessed by qRT-PCR. Only histone deacetylase (HDAC) 1, 6 and 9 mRNA levels were significantly upregulated in MSEW aortae compared to CON (17%, 29% and 67% increase, respectively, p<0.05). However, only HDAC 9 protein expression was elevated in MSEW aortae (2 fold increase from CON, n=6, p=0.01). Accordingly, histone 3 lysine acetylation was slightly decreased in MSEW aortae (16% decrease from CON, n=6, p = 0.06). Pretreatment of aortae with an HDAC inhibitor, trichostatin A (TSA), normalized ACh-induced vasorelaxation in MSEW mice (MSEW: 68% vs MSEW + TSA: 88%, p=0.02), while not affecting ACh-induced vasorelaxation in CON mice. We conclude that ELS induces endothelial dysfunction, most likely, through an HDAC 9-mediated pathway.

Abstract 141: Histone Deacetylase 1 Regulates Nitric Oxide Production and Nitric Oxide Synthase-3 Acetylation in Endothelial Cells

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Kelly A Hyndman ◽  
Dao H Ho ◽  
Jennifer S Pollock
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Histone Deacetylase ◽  
Life Stress ◽  
Trichostatin A ◽  
Early Life Stress ◽  
No Production ◽  
Histone Deacetylase 1 ◽  
Nitrite Production

Previous reports showed that NOS3 is regulated by acetylation through transcriptional mechanisms via histone acetylation or through direct lysine acetylation. Histone deacetylase (HDAC) enzymes and histone acetyltransferases (HATs) modulate acetylation processes. Recent work by our lab, demonstrated increased expression of aortic HDAC1 and HDAC6 while HATs were unchanged in a mouse model of early life stress with endothelial dysfunction. These data suggest a negative correlation between endothelial dysfunction and HDAC expression. The purpose of this study was to test the hypothesis that HDAC1 and 6 regulate endothelial NO production and/or NOS3 acetylation. Initial immunoprecipitation studies with anti-acetyl lysine and anti-NOS3 antibodies demonstrated that NOS3 is basally acetylated in primary bovine aortic endothelial cells (BAECs). Treatment with the HDAC inhibitor, trichostatin A (500 nM) for 1 hr, significantly increased NOS3 acetylation. BAECs were transfected with HDAC1, HDAC6, vector expression plasmids, or untransfected, with nitrite production determined by HPLC and NOS3 acetylation and expression probed by immunoprecipitation and Western blotting. Untransfected and vector transfected control BAECs had similar NO production (357 ± 10 and 344 ± 30 pmol/mg pr/h, respectively, N=6) as well as NOS3 acetylation (7.8 ± 1.6 and 6.8 ±0.3 AU, N=3). HDAC6 transfected BAECs had similar NO production to the control BAECs (272 ± 93 pmol/mg pr/h, N=3) with an increase in NOS3 acetylation (17.4 ± 1.7 AU, N=3). In contrast, HDAC1 overexpression significantly decreased NO production (89 ± 50 pmol/mg pr/h, P< 0.05, N=3) and reduced NOS3 acetylation (3.8 ± 0.5 A.U, N=3), P <0.05). Control transfections, HDAC6, and HDAC1 transfected BAECS all had similar NOS3 expression (10.14 ± 1.8; 9.8 ±1.6; 8.9 ± 1.5; 10.6 ± 1.0 AU, respectively, N=3). Thus, we conclude that HDAC1 regulates NO production via direct lysine deacetylation of NOS3.

Abstract 360: Early Life Stress Increases Hematocrit and Endothelin-1 in Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Dao H Ho ◽  
Jennifer S Pollock
Keyword(s):  
Endothelial Dysfunction ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Radioligand Binding ◽  
Early Life Stress ◽  
Male Mice ◽  
Endothelin 1

In humans, early life stress (ELS) is an independent risk factor for adult cardiovascular disease (CVD). We have shown that mice subjected to ELS by maternal separation with early weaning (MSEW), develop vascular endothelial dysfunction in adulthood. A marker of endothelial dysfunction and CVD is high hematocrit, an abnormally elevated level of circulating red blood cells. Hematocrit is largely regulated by erythropoietin (EPO), a protein that is released predominantly from the kidney under conditions of hypoxia. We hypothesized that MSEW increases circulating EPO and hematocrit in adult male mice. We used the MSEW model in C57BL6J mice to study the mechanisms of ELS-mediated alteration in hematocrit. MSEW litters were subjected to maternal separation 4h/day (postnatal day (PD) 2-5) and 8h/day (PD6-16), and weaned at PD17. Control (CON) litters were undisturbed until weaning at PD21. At 13 weeks of age, blood was collected from CON and MSEW male mice by cardiac puncture and lung tissue was excised. Hematocrit of MSEW mice was significantly higher than CON mice (46.2 ± 0.03 vs 43.3 ± 0.03%, p = 0.004). Plasma EPO, as measured by ELISA, was elevated in MSEW mice, however not significantly (112.89 ± 51.32 vs 61.62 ± 20.73 pg/ml, p = 0.06). We further hypothesized that MSEW enhances circulating endothelin-1 (ET-1) levels, a vasoactive peptide regulated by hypoxia and EPO. We found that plasma ET-1 was significantly increased in MSEW mice compared to CON (1.55 ± 0.41 vs 1.26 ± 0.23 pg/ml, p = 0.02). Endothelin receptor type A and B density and binding in lung, as measured by radioligand binding, was not different between groups, suggesting that increased circulating ET-1 in MSEW mice was not due to decreased ET-1 clearance in the lungs and most likely is due to increased production of ET-1. Taken together, our data suggest that MSEW-induced endothelial dysfunction may be mediated by an interplay of increased circulating red blood cells and elevated ET-1 production. Further studies are necessary to determine the exact role of these factors in this phenomenon.

scholarly journals Early life stress induces endothelial dysfunction in a mouse model of maternal separation

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Dao H. Ho ◽  
Megan L. Yu ◽  
Catalina Bazacliu ◽  
Jennifer S. Pollock
Keyword(s):  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress

scholarly journals Early life stress sensitizes the renal and systemic sympathetic system in rats

2013 ◽  
Vol 305 (3) ◽  
pp. F390-F395 ◽  
Author(s):  
Analia S. Loria ◽  
Michael W. Brands ◽  
David M. Pollock ◽  
Jennifer S. Pollock
Keyword(s):  
Blood Pressure ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Pressure Control ◽  
Sympathetic System ◽  
Renal Nerves ◽  
Adrenergic Stimulation ◽  
Pressor Responses

We hypothesized that maternal separation (MS), an early life stress model, induces a sensitization of the sympathetic system. To test this hypothesis, we evaluated the renal and systemic sympathetic system in 12- to 14-wk-old male control or MS rats with the following parameters: 1) effect of renal denervation on conscious renal filtration capacity, 2) norepinephrine (NE) content in key organs involved in blood pressure control, and 3) acute systemic pressor responses to adrenergic stimulation or ganglion blockade. MS was performed by separating pups from their mothers for 3 h/day from day 2 to 14; controls were nonhandled littermates. Glomerular filtration rate (GFR) was examined in renal denervated (DnX; within 2 wk) or sham rats using I125-iothalamate plasma clearance. MS-DnX rats showed significantly increased GFR compared with MS-SHAM rats (3.8 ± 0.4 vs. 2.4 ± 0.2 ml/min, respectively, P < 0.05), whereas DnX had no effect in controls, indicating that renal nerves regulate GFR in MS rats. NE content was significantly increased in organ tissues from MS rats ( P < 0.05, n = 6–8), suggesting a sensitization of the renal and systemic sympathetic system. Conscious MS rats displayed a significantly greater increase in mean arterial pressure (MAP) in response to NE (2 μg/kg ip) and a greater reduction in MAP in response to mecamylamine (2 mg/kg ip, P < 0.05, n = 4) monitored by telemetry, indicating that MS rats exhibit exaggerated responses to sympathetic stimulation. In conclusion, these data indicate that MS sensitizes the renal and systemic sympathetic system ultimately impairing blood pressure regulation.

scholarly journals Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner

2021 ◽  
Vol 22 (4) ◽  
pp. 1899 ◽  
Author(s):  
Hae Jeong Park ◽  
Sang A. Kim ◽  
Won Sub Kang ◽  
Jong Woo Kim
Keyword(s):  
Gut Microbiota ◽  
Relative Abundance ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Female Rats ◽  
Rrna Gene ◽  
Dependent Manner ◽  
Male And Female Rats

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1–21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1β) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1β and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

scholarly journals Maternal Separation as Early-Life Stress Causes Enhanced Allergic Airway Responses by Inhibiting Respiratory Tolerance in Mice

2018 ◽  
Vol 246 (3) ◽  
pp. 155-165 ◽  
Author(s):  
Ryusuke Ouchi ◽  
Tasuku Kawano ◽  
Hitomi Yoshida ◽  
Masato Ishii ◽  
Tomomitsu Miyasaka ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Airway Responses

scholarly journals Maternal separation in rodents: a journey from gut to brain and nutritional perspectives

2019 ◽  
Vol 79 (1) ◽  
pp. 113-132 ◽  
Author(s):  
Marion Rincel ◽  
Muriel Darnaudéry
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Human Subjects ◽  
Early Life Stress ◽  
Long Term Effects ◽  
Early Life Adversity ◽  
Critical Window ◽  
Beneficial Impact ◽  
The Impact

The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut–brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut–brain axis. Further research is required to understand the complex mechanisms underlying gut–brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.

scholarly journals Downregulation of kainate receptors regulating GABAergic transmission in amygdala after early life stress is associated with anxiety-like behavior in rodents

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jonas Englund ◽  
Joni Haikonen ◽  
Vasilii Shteinikov ◽  
Shyrley Paola Amarilla ◽  
Tsvetomira Atanasova ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Kainate Receptors ◽  
Gabaergic Transmission ◽  
Cortical Afferents ◽  
Functional Modulation ◽  
Endogenous Activity ◽  
Dependent Mechanism

AbstractEarly life stress (ELS) is a well-characterized risk factor for mood and anxiety disorders. GABAergic microcircuits in the amygdala are critically implicated in anxiety; however, whether their function is altered after ELS is not known. Here we identify a novel mechanism by which kainate receptors (KARs) modulate feedforward inhibition in the lateral amygdala (LA) and show that this mechanism is downregulated after ELS induced by maternal separation (MS). Specifically, we show that in control rats but not after MS, endogenous activity of GluK1 subunit containing KARs disinhibit LA principal neurons during activation of cortical afferents. GluK1 antagonism attenuated excitability of parvalbumin (PV)-expressing interneurons, resulting in loss of PV-dependent inhibitory control and an increase in firing of somatostatin-expressing interneurons. Inactivation of Grik1 expression locally in the adult amygdala reduced ongoing GABAergic transmission and was sufficient to produce a mild anxiety-like behavioral phenotype. Interestingly, MS and GluK1-dependent phenotypes showed similar gender specificity, being detectable in male but not female rodents. Our data identify a novel KAR-dependent mechanism for cell-type and projection-specific functional modulation of the LA GABAergic microcircuit and suggest that the loss of GluK1 KAR function contributes to anxiogenesis after ELS.

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