bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mental Stress Increases Cerebral Perfusion, More So During Hypercapnia
Authors: Shoemaker Leena , Wilson Luke , Lucas Sam , Machado Liana , Cotter James 
Published: June 2021

Acute mental stress has been shown to cause peripheral vascular dysfunction, but its effect on cerebrovasculature is unclear. Thus, the aim of this study was to examine cerebrovascular and hemodynamic responses to mental stress. Sixteen healthy participants (aged 23±4 y, 5 female) completed seated conditions of baseline, followed by low and high mental stress. Stress conditions were mental arithmetic at two levels of difficulty (i.e., counting backwards from 1000 and subtracting 13 from a frequently changing 4‐digit number), which successfully manipulated reported stress levels (p<0.001 between conditions). During each condition, end‐tidal CO2 pressure (PETCO2) was clamped at normocapnia and two elevated levels (p<0.001): 37±3, 41±1 and 46±1 mm Hg. Middle cerebral artery blood velocity (MCAv) was measured using transcranial Doppler ultrasound, and right prefrontal cortex hemodynamics measured using near‐infrared spectroscopy (NIRS). NIRS provided variables of oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (HHb), total hemoglobin (tHb), and depth‐resolved measures of tissue oxygenation (total oxygenation index, TOI). Blood pressure was measured beat‐by‐beat using finger photoplethysmography, to calculate mean arterial pressure (MAP). Stroke volume and cardiac output (Q̇) were derived with Modelflow. Cerebrovascular reactivity to CO2 (CVRCO2, ΔMCAv/ΔPETCO2), cerebrovascular conductance (CVC, MCAv/MAP), and total peripheral resistance (TPR, MAP/Q̇) were calculated. Effects of mental stress and CO2 were assessed using 2‐way repeated measures ANOVA. The acute mental stress increased MCAv, and more so at higher PETCO2 (interaction: p=0.015). No other physiological variable showed interactive responses (p>0.069). Compared to baseline, low stress increased HR, MAP, TOI, HbO2, and decreased HHb (all p<0.003), but these variables were not altered thereafter with high stress (p>0.05; low vs. high stress). In contrast, CVRCO2 was elevated during high stress only (p=0.017 vs. baseline; p=0.706 for low stress vs. baseline). Finally, neither stress nor CO2 significantly influenced TPR (p≥0.241). In conclusion, mental stress increased MCAv and this was potentiated during hypercapnia. Increased cerebral perfusion during mental stress was mediated by cardiac‐driven increases in MAP. Hypercapnic‐induced blunting of cerebral autoregulation indicates that there may be a greater risk of cerebral overperfusion (e.g., hemorrhagic stroke) as a consequence of mental stress when innate cerebral autoregulation processes are impaired (e.g. early morning).Support or Funding InformationInternal postgraduate research fund ‐ The School of Physical Education, Sport and Exercise SciencesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Blood Pressure in Wild‐type and Ts65Dn Mice at 6 Months of Age
Authors: DeRuisseau Lara R. , Buchholz Haley , Purdy Rebecca , Receno Candace , Cunningham Caitlin 
Published: June 2021

Down syndrome (Ds) results from triplication of the 21st chromosome, and is estimated to occur 1 in every 700 births in the United States. Many people with Ds exhibit cardiovascular challenges including pulmonary hypertension and lower resting blood pressure. We tested the hypothesis that Ts65Dn mice, a model of Ds, would exhibit lower blood pressure compared to wild‐type mice. The CODA volume‐pressure tail cuff system by Kent Scientific (Torrington, CT) was used to quantify systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) in 6–month wild‐type (n=9) and Ts65Dn (n=7) male mice. Two trial days were administered for each mouse that included 15 inflation/deflation cycles of the cuff on each day. The trial was considered successful if ≥7 of the 15 cycles were accepted by the software. The mean of the 7–15 cycles was calculated for each mouse (DBP, SBP and MAP separated). If the 2nd trial mean differed by >10 mmHg for SBP the mouse was excluded from the analysis. Data are shown as wild‐type vs. Ts65Dn; MEAN ± SD; * = p<0.05. Ts65Dn mice displayed a reduced SBP (104 ± 9 vs. *96 ± 4 mmHg). DBP (77 ± 9 vs. 69 ± 5 mmHg) and MAP (85 ± 9 vs. 78 ± 4 mmHg) were not different in this early analysis. These data suggest that Ts65Dn mice may be an appropriate model to use in understanding cardiovascular function in Ds. Further investigation is warranted to confirm these findings across the lifespan of wild‐type and Ts65Dn mice.Support or Funding InformationFunded by 1 R15 HD076379‐01A1 (LRD), HKB supported by the Ignite fellowship and Le Moyne College Student Research Committee, CNR supported by 1 R15 HD076379‐01A1S1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Hemodynamic Hyper‐reactivity to Acute Stress in Individuals Reporting Adversity during Childhood: Role of Endothelin‐1
Authors: Tucker Matthew A. , Looney Jacob , Blackburn Marsha , Pollock Jennifer S. , Pollock David M. , Harris Ryan A. 
Published: June 2021

Individuals exposed to adverse childhood experiences (ACE) have an increased risk of developing cardiovascular disease versus those with no ACE. Moreover, these individuals also exhibit an exaggerated blood pressure response to an acute sympathetic stressor; a response that is associated with an increased risk of developing hypertension and shown to be mediated by endothelin‐1 (ET‐1) in animal models. The role of ET‐1 as a modulator of the hemodynamic response to acute stress in humans with high ACE, however, is unknown.PurposeTo compare hemodynamic and plasma ET‐1 responses to a cold pressor test (CPT) in individuals who reported high ACE versus matched controls with no reported ACE.Methods14 participants volunteered for this investigation; 7 of which reported an ACE score ≥4 via questionnaire (HI‐ACE; 5 men, 2 women) and 7 control participants (CON) who were matched for age, ethnicity, sex, and body composition. All participants underwent a CPT protocol which consisted of a 5 min baseline followed by immersion of the right hand up to the wrist in ice water (~2°C) for 3 min. Hemodynamic parameters including total peripheral resistance index (TPRI), cardiac index (CI), and systolic/diastolic blood pressure (SBP/DBP) were measured throughout the protocol using beat‐to‐beat monitoring of finger arterial pressure (Finapres NOVA). Plasma concentrations of ET‐1 were determined at baseline and during the second minute of the CPT.ResultsThere were no differences (all p>0.05) between groups in age, ethnicity, sex, body composition, or fasting blood glucose. Similarly, there were no differences (all p>0.05) in baseline values of TPRI (0.39 ± 0.31 vs. 0.43 ± 0.25 mmHg/ml/m2), CI (3.5 ± 0.8 vs. 3.5 ± 0.6 L/min/m2), SBP (134 ± 14 vs. 133 ± 12 mmHg), or DBP (83 ± 10 vs. 85 ± 11 mmHg) between HI‐ACE and CON. During CPT, a significantly greater increase in SBP (48 ± 20 vs. 29 ± 10 mmHg; p=0.041) and DBP (35 ± 15 vs. 19 ± 5 mmHg; p=0.028) occurred in HI‐ACE compared to CON. While concentrations of ET‐1 at baseline were similar between HI‐ACE and CON (1.28 ± 0.21 vs. 1.22 ± 0.33 pg/ml, respectively), the ET‐1 response during CPT tended (p=0.098) to be higher in HI‐ACE versus CON (Δ1.12 ± 0.03 vs. Δ0.50 ± 0.37 pg/ml).ConclusionThese data suggest that greater plasma concentrations of ET‐1 accompany the exaggerated hemodynamic response to a CPT in individuals who reported high ACE. Future studies are warranted to further elucidate the role of ET‐1 as a mediator of hemodynamic responses to acute stress in individuals with high ACE.Support or Funding InformationSupported in part by NIH/NHLBI P01HL06999.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Responses in the Splenic CD4+ T Cell Proteome Following Ang II‐Induced Hypertension in VCD‐Treated Menopausal Mice
Authors: Husband Nathaniel A. , Moffett Caitlin , Romero‐Aleshire Melissa J. , Uhlorn Joshua A. , Uhrlaub Jennifer , Barker Natalie , Nunez Franchesca , Nikolich‐Zugich Janko , Langlais Paul , Brooks Heddwen L. 
Published: June 2021

Cycling female mice are protected against Angiotensin II (Ang II) hypertension, and inducing ovarian failure (menopause) eliminates this protection. T lymphocytes are required for the development of Ang II hypertension in male mice, however premenopausal females are resistant to T cell‐induced hypertension. Following menopause (loss of estrogen) resistance is lost, allowing activation of T cell‐induced hypertension in postmenopausal females. The purpose of this study was to identify, in vivo, T cell‐specific proteome responses to Ang II, before and after menopause. 10‐week‐old C57BL/6 female mice received i.p. 4‐vinylcyclohexene diepoxide (VCD) injections for 20 consecutive days to induce ovarian failure (VCD menopause model). Cyclicity was monitored daily via vaginal cytology. Once in menopause, Ang II was infused (800 ng/kg/min) for 14 days, which has been shown to cause an increase in SBP of 25 mmHg. Ang II in VCD‐treated menopausal females (VCD/AngII) resulted in significantly decreased heart rates versus controls (Control 682 ± 5.6 vs. VCD/AngII 592.5 ± 28.5, p < 0.05). Splenic CD4+ T cells were purified via negative immune‐magnetic selection and CD4+ purity was measured via flow cytometry (>90% purity). Proteomic analysis was performed on control, pre‐menopausal/Ang II and VCD/AngII mice (n=4 per group). Protein lysates from the CD4+ T cells were separated by SDS‐PAGE and subjected to in‐gel tryptic digestion followed by tandem mass spectrometry analysis, resulting in 7,123 proteins identified across the entire experiment. Quantitative proteomics were performed via label‐free quantification using Progenesis software‐based extracted ion abundance. Of the 5,857 proteins identified with two or more unique peptides, 474 of the proteins exhibited significant abundance differences between control, Ang II and VCD/Ang II groups as assessed by One‐Way ANOVA statistical analysis (p ≤ 0.05). Gene Ontology (GO) enrichment analysis of these 474 proteins identified 159 GO biological pathways that were significantly overrepresented (p ≤ 0.05). Pathways associated with increased inflammation and reduced inhibition of inflammatory cytokines were among those identified. Using IHC we show that renal macrophage infiltration is significantly increased in VCD/Ang II mice compared to Ang II and control groups. Overall, our data suggests that following Ang II infusion, splenic T cells are differently impacted by the loss of estrogen, leading to an increased pro‐hypertensive cytokine milieu compared to pre‐menopausal Ang II infused mice.Support or Funding InformationR01HL131834 (HLB)Sarver Heart Center Endowment for Women's Health Research (HLB)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibition of the RNA binding protein HuR reduces cardiac cell death following ischemia/reperfusion injury
Authors: Slone Samuel , Anthony Sarah R. , Lanzillotta Lindsey , Nieman Michelle L. , Green Lisa C. , Lorenz John N. , Tranter Michael 
Published: June 2021

Despite medical advances, ischemic cardiac injury (ischemia/reperfusion (I/R) injury or myocardial infarction) remains a leading cause of morbidity and huge economic burden in the United States. It is known that the extent of total damage to the heart following I/R injury is directly linked to the percentage of affected individual cardiac myocytes that undergo apoptotic cell death. RNA binding proteins are becoming recognized as potential mediators of cardiac physiology and pathology, but the role of HuR, an RNA binding protein highly expressed in myocytes, in acute cardiac I/R injury is unknown. It is widely accepted that after an ischemic injury, reperfusion, the return of blood flow and therefore oxygen, introduces reactive oxygen species (ROS) that further activates downstream pro‐apoptotic pathways. We have previously shown HuR to be activated downstream of p38 MAPK in cardiac myocytes; since p38 MAPK is known to be downstream of ROS, we postulated that HuR is a potential mediator of apoptotic gene expression during cardiac I/R injury.To address the functional role of HuR in I/R, we utilized an inducible cardiomyocyte‐specific HuR deletion mouse (iCM‐HuR−/−) and subjected these mice to 30 minutes of LAD (left anterior descending artery) ligation followed by 24 hours of reperfusion. Analysis of infarct size showed that iCM‐HuR−/− mice had a significantly smaller infarct compared to control mice (41% infarct/risk in iCM‐HuR−/− vs. 51% infarct/risk in control, N=3, P<0.05). To identify an underlying mechanism for this cardioprotective effect, we performed simulated I/R (simI/R) in vitro on neonatal rat ventricular myocytes (NRVMs) by subjecting them to 6 hrs of simulated ischemia (glucose deprivation and hypoxia at ≤1% O2) followed by 24 hrs of reperfusion (reoxygenation and reintroduction of glucose). Similar to our in vivo results, siRNA‐mediated knockdown or pharmacological inhibition of HuR significantly reduced simI/R‐induced cell death and caspase‐3 activity. We also observed an increase in expression of key apoptotic genes (Bcl‐2, Bad, and Bax) in NRVMs following simI/R, and ongoing work will identify the specific role of HuR in mediating expression of these genes.In conclusion, our results suggest that ablation of HuR results in a significant reduction in infarct size following I/R injury through a reduction in caspase 3‐dependent apoptotic cell death.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endoplasmic Reticulum Stress Mediated Inflammation may involve in Doxorubicin‐induced Cardiomyopathy
Authors: Bagchi Ashim K. , Vashisht Vandana , Akolkar Gauri , Singal Pawan K. 
Published: June 2021

Many subcellular signaling pathways have been proposed to explain myocardial dysfunction triggered by doxorubicin (Dox). Although endoplasmic reticulum (ER) stress has been suggested to be an important factor in myocardium dysfunction, its role in Dox‐induced cardiomyopathy (DIC) has not been fully understood. Here, we show that ER stress promotes inflammation through iNOS‐regulated Toll‐like receptor 2 (TLR 2) activation in DIC. Cardiomyopathy in male Wistar rats was produced by repeat six equal injections of Dox (each 2.5 mg/kg ip) over three weeks for a cumulative dose of 15 mg/kg body wt. Controls were given only saline. Hearts from these animals were used two weeks after the last treatment. ER stress in the DIC hearts was indicated by an upregulation of binding immunoglobulin proteins (Bip). Furthermore, there was an increased unfolded protein response and dimerization of Bip with ATF6. This increase in ER stress in DIC promoted iNOS activity. The latter was associated with increased expression of TLR2 and TRAF2 together with increased NFκB105/50 expression. This in‐turn promoted pro‐inflammatory cytokines TNF‐ α, and IL‐1α in the myocardium. Overall these data indicate that inflammation, mediated by ER stress, via a direct interaction of Bip and ATF6, upregulates iNOS as well as pro‐inflammatory cytokine production in DIC. Manipulation of this complex signaling pathway may be of therapeutic benefit to prevent cardiomyopathy due to Dox.Support or Funding InformationSupported by CIHR and Research ManitobaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High glucose induces Glucose transporter‐2 (GLUT2), but not Na‐glucose cotransporter‐1 (SGLT1) mediated glucose absorption
Authors: Walton Nerissa , Rhodes Ryon Sun , Rajendran Vazhaikkurichi M. , Coon Steven D. 
Published: June 2021

BackgroundGlucose dependent insulinotropic peptide (GIP) is a hormone that has a cyclic pathway in the stimulation of glucose transport. GIP increases transport of glucose, which in turn stimulates GIP secretion. This cycle increases the jejunal absorption of glucose, which stimulates insulin release. High glucose results in excess GIP secretion that causes unusually high glucose absorption and high blood glucose that stimulates insulin release that causes insulin insensitivity. Presence of high blood glucose and insulin lead to obesity and Type‐2 diabetes. Although SGLT1 is the primary apical glucose absorptive process, GLUT2 has been localized on the intestinal apical membranes of obese human and mouse models. However, signaling mechanisms of how GIP regulates glucose transporters in the presence of normal versus high levels of extracellular glucose concentrations is not known.HypothesisExtracellular glucose concentration that alters cellular GIP level would regulate glucose transporters on to the apical membrane of differentiated cells.MethodsIntestinal epithelial crypt cell‐6 (IEC6 cells) where grown 5‐days post confluent on transwell snapwells using standard DMEM media supplemented with 5% FBS and either 4.5 or 0.45 g/liter of glucose for high and low glucose, respectively. Mucosal to serosal (m‐s) glucose fluxes were measured across IEC6 cell layers that were mounted under voltage clamp conditions in Ussing chambers. Short circuit currents were measured to distinguish the SGLT1 (i.e. electrogenic) and GLUT2 (i.e. electroneutral) mediated glucose absorption. Apical membranes were isolated from IEC6 cell monolayers using a biotinylation technique. Western blot analyses were performed using SGLT1 and GLUT2 antibodies.ResultsGlucose absorption is substantially higher in IEC6 cells that were grown in high glucose medium compared to that grown in low glucose medium. In contrast to increased rate of glucose absorption, Isc is not significantly altered as an indication that high glucose increased GLUT2 mediated, but not SGLT1 mediated glucose absorption in IEC6 cells. Western blot analyses revealed that GLUT2, but not SGLT1 specific protein expression is increased on the apical membrane of IEC6 cells grown in the high glucose medium.ConclusionsHigh extracellular glucose environment stimulates GLUT2, but not SGLT1 expression and GLUT2 mediated glucose absorption in intestinal epithelial cells.SpeculationWe speculate that GLUT2 might be regulated similarly in in the villus cells of mouse intestine.Support or Funding InformationIMBRE grant #G110‐18‐W6619This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Protective Role of TRPC6 Knockout in the Progression of Diabetic Nephropathy
Authors: Spires Denisha , Ilatovskaya Daria V. , Levchenko Vladislav , Palygin Oleg , Staruschenko Alexander 
Published: June 2021

Diabetic nephropathy (DN) is a chronic kidney pathology that leads to end stage renal disease (ESRD). It was previously found that a gain‐of‐function mutation in the Transient Receptor Potential Canonical 6 (TRPC6) channel, a non‐selective cation channel that is highly permeable for calcium ions, causes Focal Segmental Glomerulosclerosis (FSG) that is characterized with podocyte loss. Previous studies from our laboratory indicate that there is an association between the development of DN and over‐activation of the TRPC6 channel. We have demonstrated that there is an increase in TRPC6 expression and activity in the streptozotocin (STZ)‐induced diabetic Dahl Salt‐sensitive (SS) rat, an established model of type 1 DN. We have created the TRPC6 knock‐out on a SS rat background (SSTRPC6−/−), and test the hypothesis that the deletion of TRPC6 will protect podocytes and glomeruli during the development of DN. Four groups of animals – control SS, SSTRPC6−/−, and STZ‐treated SS and SSTRPC6−/− – were utilized in this study. Diabetes development was monitored for 11 weeks after STZ injection with periodic weight, glucose, and urinary output measurements. Glomerular filtration rate (GFR) was measured and tissue collections were made at the end of the protocol. Freshly isolated glomeruli of perfused kidneys were used from all four groups for either electron microscopy or confocal fluorescence microscopy to assess the foot process effacement and basal level of intracellular calcium ([Ca2+]i), respectively. Histochemical analysis of whole kidney slices was done to assess renal injury. There was a decrease in urinary output (49±29 vs 73±39 mL/day/100g BW) and a trend for blunted increase in albuminuria (97±34 vs 112±19 mg/day x 100g BW) in the STZ‐treated SSTRPC6−/− rats compared to the STZ‐SS animals. There was no significant difference in GFR between either of the 4 experimental groups; however there does appear to be a trend for hyperfiltration in the STZ‐treated animals. Importantly, pathological increases in basal [Ca2+]i levels and foot process damage of podocytes during the development of DN was attenuated in the STZ‐treated SSTRPC6−/− animals. Overall, our data indicates that inhibiting the TRPC6 channel may have renoprotective effects and the potential to lead to the development of new pharmacological tools to treat or prevent the progression of DN and kidney damage.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.