bluuebunny/crossref_metadata_2025 huggingface dataset:
Mineralocortidoid Receptor Mediates Uremic Serum‐Induced Increase in Endothelial Cell Dysfunction
Authors: de la Rosa Diego Alvarez , Cazaña‐Perez Violeta , Giraldez Teresa , Navarro‐Gonzalez Juan F. , Kusche‐Virhog Kristina
Published: June 2021

Patients with chronic kidney disease (CKD) have a markedly increased incidence of cardiovascular disease (CVD) and mortality compared with the age‐matched general population. The high concentration of circulating uremic toxins in CKD patients leads to vascular inflammatory, thereby inducing endothelial dysfunction, which is associated with CVD development and progression. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. The aim of our study was to analyze the influence of CKD in the expression of endothelial ion channels and its potential modification by mineralocorticoid receptor (MR) inhibition, which would consequently affect endothelial cell function. To that end we used primary human endothelial cells cultured in medium supplemented with pooled sera from either healthy or uremic patients undergoing dialysis. To obtain a complete profile of ion channel subunit expression in both cellular types, we performed high‐throughput qPCR of 92 ion channel genes using a custom‐designed Taqman low‐density array card. In addition, we characterized the influence of uremic serum on nitric oxide (NO) production and measured cortical stiffness using atomic force microscopy. Our data show that uremic serum potently increased MR expression. In addition, it induced remodeling of ion channel expression patterns, including increased expression of αENaC, a known transcriptional target of MR that promotes cortical stiffness and endothelial dysfunction. Exposure of endothelial cells to uremic serum significantly decreased NO production and produced stiffening of the endothelial cell cortex, which was prevented by inhibition of MR using spironolactone. Our data identifies MR as a possible mediator of uremia‐induced endothelial dysfunction and supports the proposed beneficial effects of MR inhibition during CKD.

Support or Funding Information

This work was supported by a grant from Ministerio de Economía e Innovación (MINECO, grant BFU2016‐78374‐R) to D.A.R.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Timing of Blood Pressure Rhythms Predict Risk of Renal Injury in the Dahl Salt‐Sensitive Rats
Authors: Chen Daian , Booth John N. , Houchin Colton , Colson Jackson C. , Jin Chunhua , Cowley Allen W. , Geurts Aron , Muntner Paul , Young Martin E. , Pollock David M. , Pollock Jennifer S.
Published: June 2021

Salt‐sensitive individuals have higher susceptibility for dysfunctional diurnal blood pressure rhythms, development of hypertension and renal injury. The aim of this study was to elucidate genetic determinants of diurnal excretion of renal injury markers and timing of systolic BP (SBP) peak and trough patterns in 4 rat models of salt‐sensitivity. We utilized male Dahl salt‐sensitive (SS) rats, NADPH oxidase p67phox knockout in SS (SS.p67phox−/−), introgression of chromosome 13 from Brown‐Norway rats into SS (SS.BN13), and introgression of 16Mbp section of BN13 (SS.BN‐(D13Rat151‐D13Rat197)) in SS (SS.Line26). Male, 12–14 week old rats (n=7–14) were maintained on normal salt (NS; 0.4% NaCl) and then fed high salt (HS; 4% NaCl) diet for 7 days (Dyets, AIN‐76A). Telemetry was used to continuously measure SBP, heart rate and locomotor activity. On NS, 24‐hr SBP was 155.9 ± 0.2 mmHg (SS), 141.6 ± 0.3 mmHg (SSp67phox−/−), 145.5 ± 0.4 mmHg (SS.BN13), and 155.2 ± 0.2 mmHg (SS.Line26). The average 24‐hr SBP in rats on high salt diet was 173.3 ± 0.5 mmHg, 152.2 ± 0.5 mmHg, 158.5 ± 0.6 mmHg, and 171.0 ± 0.6 mmHg, respectively. Eating HS did not change the timing of peak and trough SBP rhythms within each genotype. Furthermore, there were no differences in timing of peak timing of SBP across genotypes on either diet. Similarly, there was no difference in timing of trough SBP across genotypes on NS. However, HS delayed the timing of trough SBP in SS (n=14) by 5.3 hours compared to SS.p67phox−/− (n=12, p<0.001) and by 2.6 hours compared to SS.BN13 rats (n=7, p=0.036). Timing of trough SBP was similar between SS.Line26 (n=12) and SS rats. Heart rate and locomotor activity were not significantly different across genotypes or diets. On HS diet, SS.p67phox−/− (n=8) had lower proteinuria and albuminuria than SS (n=14) and SS.Line26 (n=12) during the active phase (p<0.0001). On HS, proteinuria, albuminuria, and nephrinuria were highest in SS.Line26 compared to SS, SS.p67phox−/−, and SS.BN13 (n=7) during active phase (p<0.01). Excretion of kidney injury marker 1, KIM1, was significantly higher in SS than SS.Line26, SS.BN13, and SS.p67phox−/− (p<0.005). In summary, SS and SS.Line26 rats have delays in the inactive (trough) timing of SBP, which is associated with proximal tubular injury in SS and glomerular injury in SS.Line26 rats. These findings indicate that rat chromosome 13 has a role at least in part, in the timing of SBP and risk of kidney injury in the SS rat.

Support or Funding Information

American Heart Association Strategically Focused Research Network ‐ Hypertension (15SFRN2390002)

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in the Development of Renal Injury in Obese Dahl Salt‐Sensitive Leptin Receptor Mutant Rats During Prepubertal Obesity
Authors: Poudel Bibek , Shields Corbin Anthony , Cornelius Denise C. , Williams Jan M.
Published: June 2021

Recent studies show that prepubertal obesity (PPO) is associated with increased risk of renal injury in children. Furthermore, nearly 40% of obese children develop microalbuminuria. Additionally, studies examining the impact of sex on the development of renal injury associated with PPO have been limited. Recently, we reported that, prior to puberty, male Dahl salt‐sensitive leptin receptor mutant (SSLepR mutant ‐ PPO model) rats display proteinuria and podocyte injury by 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. However, female PPO rats were not examined during the same time period. Therefore, in the current study, we investigated whether there were sex differences during the development of renal injury associated with prepubertal obesity. Proteinuria was significantly higher in female and male PPO rats as opposed to the values observed in Control rats at 4 weeks of age (65±12 and 64.7±13 vs 2±1 and 2±0.3 mg/day, respectively, n=4). While we observed minimal increases in proteinuria in Control rats at 8 weeks of age, proteinuria increased to 266.6±65 and 376±56 mg/day in female and male PPO rats, respectively. The kidneys from the PPO rats displayed significant glomerular injury and marked renal fibrosis when compared to the values measured in Control rats. Interestingly, the development of proteinuria and glomerular injury in the PPO model was associated with increased infiltration of CD68+ macrophages expressing Lamp2 and CD36, markers for lysosomes and fatty acid translocase, respectively. Additionally, we assessed renal inflammation via the Bio‐Plex Pro Rat Cytokine 23‐Plex Immunoassay and observed that macrophage inflammatory protein‐3a (MIP‐3a) levels were significantly elevated in both female and male PPO rats (3059±364 and 2545±333 ng/mg of protein, respectively) compared to the values measured in Control rats (1579±291 and 1138±95 ng/mg of protein, respectively). Overall these data indicate that the early development of renal injury in the PPO model might be due to macrophage infiltration stimulating progressive proteinuria independent of hypertension and diabetes.

Support or Funding Information

This study was supported by P20GM104357 and R01 DK109133‐01.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
EFFECT OF DENERVATION ON REDOX‐REGULATION IN SKELETAL MUSCLE
Authors: Scalabrin Mattia , Pollock Natalie , McArdle Anne , Jackson Malcolm Joseph , Vasilaki Aphrodite
Published: June 2021

Changes in skeletal muscle mass and function occur during aging and are accompanied by loss of integrity and stability of the neuromuscular junction. Previous studies from our group have shown a significant increase in the mitochondrial generation of hydrogen peroxide (H202) and other peroxides in denervated muscle fibers. The mechanisms of generation of these peroxides and the effect on muscle responses are unknown. Our aim was to determine the effect of denervation on proteins that may contribute to peroxide release and proteins that regulate redox responses.

The Anterior Tibialis (AT) and Extensor Digitorum Longus (EDL) muscles of wild type mice were denervated under anaesthesia by surgical removal of a small section of the peroneal nerve. Western blotting and immunohistochemical techniques were used to examine protein contents. AT and EDL muscles of thy‐1YFP mice, in which YFP expression in neuronal cells allow visualisation of the muscle innervation, were also denervated and used for morphological examination and analysis of muscle mitochondrial peroxide release.

Previous work from our group has shown that, following denervation, hydrogen peroxide can be generated by several sources within mitochondria (Pollock et al, Free Rad. Biol. Med 2017) and the current data show that the increased peroxide generation was maintained to 21 days and was associated with a significant increase in Monoamine Oxidase A and NADPH Oxidase components. An increased content of proteins involved in the activation of the NADPH oxidase complex such as Peroxiredoxin 6 and Phospholipase A2 was also observed together with a significant increase in the content of several enzymes involved in the protection of cells against oxidative damage. Oxyblot analysis to assess the levels of carbonylation, showed that by 7 days post‐denervation there was a significant increase in protein carbonylation of low molecular weight (25–35 kDa) proteins. Morphological analysis indicated a progressive significant loss of muscle mass in the AT muscle from 7 days up to 21 days following denervation due to fiber atrophy without fiber loss. These results support the possibility that (at least initially) the increase in peroxide production may stimulate adaptations to protect the muscle fibers but, together with data on structural changes indicating significant fiber atrophy from 7 days after denervation, increased peroxide generation over the longer term may activate degenerative processes, such as apoptosis of the denervated muscle fibers.

Support or Funding Information

This project was funded by the US National Institutes of Health (NIA) and the Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Consecutive, Long‐Duration Hyperoxic Water Immersions on Neuromuscular Performance in Well Trained, Male Divers
Authors: Myers Christopher , Kim Jeong‐Su , Florian John
Published: June 2021

PURPOSE

The main objective of this study was to investigate the physiological effects of single and repetitive diving‐induced hyperoxic conditions on neuromuscular performance at 1.35 atmospheres absolute (ATA). We hypothesized that following five days of consecutive, resting, long‐duration hyperoxic water immersion (WI)s, neuromuscular performance would be reduced with a longer recovery period in comparison to normoxic WIs at 1.35 ATA.

METHODS

Throughout a dive week (DW), twenty‐eight healthy, active male divers [30±1 (24–43)years; mean ± SEM] completed five consecutive 6‐hour resting WIs with 18‐hour surface intervals while breathing compressed atmospheric air (Air: n=15) or 100% oxygen(O2:n=13) at 1.35 ATA. Skeletal neuromuscular performance was assessed immediately before and after each WI, and 24 and 72 hours after the final WI. Assessments included knee extension and elbow flexion maximum voluntary isometric contractions (MVIC) and maximal isokinetic (IK) contractions, as well as measurement of maximum handgrip strength (MHG). Simultaneously, surface electromyography (sEMG) amplitude of the vastus lateralis, rectus femoris, vastus medialis, biceps brachii, and brachioradialis was measured.

RESULTS

Significant decreases were seen in maximal strength performance on WI 3 (MVIC knee extension: 3.4%, p<0.001; O2: 4.3%, p=0.016; MVIC elbow flexion: 3.5%, p=0.002, combined group result) with recovery occurring by WI5. The O2 group knee extensor neuromuscular activation decreased by 10% throughout the DW and remained reduced by 14% through the 72‐hr post‐WI. The Air group neuromuscular activation increased throughout the DW but returned to baseline by 72‐hr post‐dive. Combined group maximal IK elbow flexion and MHG strength performance decreased by 4% and 5%, respectively, throughout the DW (WI1> WI3 and WI5, p<0.001).

CONCLUSION

Consecutive, resting, long‐duration normoxic WIs cause noticeable decrements in muscular strength performance after three days of WIs with recovery seen by 24‐hr post‐WI. Hyperoxic WIs caused significant reductions to neuromuscular activation. Future research should examine the causes of hyperoxia‐induced decreased neuromuscular activity.

Support or Funding Information

Office of Naval Research (ONR) Award Number N000141612112 and NAVSEA DSBDP N0002416WX02277

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Work of Breathing in Obese Men with and without Dyspnea on Exertion
Authors: Bernhardt Vipa , Bhammar Dharini M. , Marines‐Price Rubria , Babb Tony G.
Published: June 2021

INTRODUCTION

Breathlessness during exercise, or dyspnea on exertion (DOE), is a common complaint in otherwise healthy obese adults. It is possible that the higher perception of breathlessness is due to a higher work of breathing. Thus, we investigated whether obese men with high DOE (+DOE) have a higher work of breathing (i.e., oxygen cost) than obese men with a low DOE (−DOE).

METHODS

27 obese men underwent underwater weighing and a 6‐min constant load submaximal cycling exercise at 105 W. They also performed eucapnic voluntary hyperpnea (EVH) to determine the oxygen cost of breathing. Participants were classified as +DOE, if their Rating of Perceived Breathlessness (RPB, Borg 0–10 scale) was ≥ 4 (n = 16) and as −DOE if RPB was ≤ 2 (n = 11) during minute 6 of the exercise test. The oxygen cost of breathing was obtained by calculating the slope of the oxygen uptake (ml/min) vs. ventilation (L/min) relationship at rest and during EVH at 60 and 90 L/min. RPB was also collected during the last minute of each EVH trial. Following the 90 L/min EVH trial, participants were asked to choose the “top 3 descriptors that best describe[d] the respiratory sensations [they] felt during the test” from a list of 15 descriptors. Data were analyzed between groups by independent t‐test.

RESULTS

There were no significant differences between +DOE and −DOE groups in age, BMI, or body fat percentage, respectively (+DOE: 35 ± 6 yr, 36 ± 5 kg/m2, 39 ± 5%; −DOE: 32 ± 6 yr, 35 ± 3 kg/m2, 37 ± 6%; mean ± SD, p > 0.05). Breathlessness ratings during each level of EVH was significantly greater in the +DOE than the −DOE group (p < 0.01). However, there was no significant difference in the oxygen cost of breathing between +DOE (2.05 ± 0.63 ml/L) and −DOE (1.99 ± 0.78 ml/L, p > 0.05). Eleven of the 16 men +DOE felt that their breathing required effort or work (only 3 of the 11 men −DOE).

CONCLUSIONS

The otherwise healthy obese men who rated higher breathlessness during exercise also perceived higher breathlessness during the EVH trials. The increase in the intensity of breathlessness was not due to an increased oxygen cost of breathing. Even though the measured work of breathing was not different, the +DOE group more frequently described their breathing to require more work/effort; this perception of effort may be due to changes in neural transmission in the brain, such as a reduced gating of respiratory sensations related to the work of breathing.

Support or Funding Information

Supported by NIH Grant R01 HL096782 and King Charitable Foundation Trust.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cough response to sulfur dioxide inhalation challenge is enhanced by tumor necrosis factor alpha: a primary role of vagal bronchopulmonary C‐fibers
Authors: Lin Ruei‐Lung , Zhang Cheng , Khosravi Mehdi , Lin An‐Hsuan , Athukorala Ashami , Lee Lu‐Yuan
Published: June 2021

Tumor necrosis factor alpha (TNFα), a pro‐inflammatory cytokine, plays a significant role in the pathogenesis of asthma. We recently reported that TNFα pretreatment elevated the sensitivities of vagal bronchopulmonary C‐fibers and silent rapidly adapting rectors (RARs) to capsaicin (Front. Physiol. 2017). In this study, we investigated the effect of TNFα on cough response to sulfur dioxide (SO2), a common irritant gas, and the relative contributions of these vagal afferents. Our results showed: 1) Inhalation of SO2 (300 and 600 ppm; 8 min each) consistently elicited coughs in a concentration‐dependent manner in awake mice moving freely in a recording chamber; coughs were recorded via telemetry sensors implanted in the intrapleural space. The cough frequencies during and immediately after the SO2 inhalation challenges increased markedly in the same animals after TNFα (10 μg/ml; 0.03 ml) was administered into the lung by intratracheal instillation, and this increase in cough sensitivity sustained for >7 days after the TNFα pretreatment. In contrast, the cough response to SO2 inhalation challenges did not change after pretreatment with vehicle (0.03 ml of PBS) in a matching group of control mice. 2) In single‐fiber recording experiments in anesthetized mice, the same SO2 inhalation challenges (for 8 min) evoked a pronounced stimulatory effect on C‐fiber afferents, reaching a peak in 1–4 min. The increased fiber activity was concentration dependent and lingered for several more minutes after the termination of SO2 challenge. This stimulatory effect of SO2 was significantly elevated in the TNFα‐treated mice. 3) The same SO2 inhalation challenges, either 300 or 600 ppm, did not activate any of the silent RARs in vehicle‐treated mice, and only 600 ppm SO2 caused a very weak stimulation in 2 out of 7 of these silent RARs in TNFα‐treated mice. 4) Inhalation of SO2 (300 or 600 ppm) consistently induced an inhibitory effect on both slowly adapting receptors and phasic RARs; these afferents ceased to discharge completely in 1–5 min after the onset of SO2 (600 ppm) inhalation challenge, and a majority of them slowly returned to controls after resuming air breathing for >1 hr. No detectable difference in this inhibitory effect was found between TNFα‐ and vehicle‐treated mice. In conclusion, the cough response to SO2 inhalation challenge is enhanced by the TNFα pretreatment in wake mice, and an increase in the bronchopulmonary C‐fiber sensitivity to SO2 is primarily responsible.

Support or Funding Information

NIH grant AI123832

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of distention in swallow phase transition
Authors: Huff Alyssa , Reed Mitchell , Pitts Teresa
Published: June 2021

The effect of pharyngeal and esophageal distention on swallow phase transition has not been fully elucidated. In quadrupeds we hypothesize pharyngeal to esophageal (P:E) ratio is dependent on distention of the pharynx and/or esophagus to trigger a phase transition. To this effect videofluoroscopy was performed on 8 cats using liquid and puree consistencies laced with 40% barium. Awake cats were given 30 seconds after food/liquid presentation to initiate eating/drinking. Using MicroDicom viewer software (MicroDICOM; Sofia, Bulgaria) diameter was calibrated using an object placed in the viewing field (i.e. dime). The diameter of the pharynx, upper esophageal sphincter opening, and bolus size in the esophagus were measured. There was a significant difference between the tolerated pharyngeal distention between liquid (9.5 ± 1.9 mm) and puree (12.6 ± 2.5 mm) boluses (p=0.01), as well as esophageal distention between liquid (6.5 ± 1.9 mm) and puree (8.3 ± 2.2) boluses (p<0.05). The average distention of the UES was not significantly different (p> 0.05) with a diameter of 7.8 ± 2.0 mm for liquid versus 9.0 ± 2.0 mm for puree. The ratio of pharyngeal to esophageal phase swallows range from 2–6 in liquid boluses and 1–3 in puree boluses. The variable pharyngeal to esophageal phase ratio supports the hypothesis that transition through each phase of swallow is driven by distention of the pharyngeal and esophageal walls and not by a set P:E ratio.

Support or Funding Information

Supported by R00‐ HL 111215 and The Kentucky Spinal Cord and Head injury Trust.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
FK506‐binding protein 51 plays a role in pulmonary endothelial cell phenotype switching
Authors: Brown Jonathan R. , Morrow Rebekah L. , Morrow K. Adam , Vasauskas Audrey A.
Published: June 2021

It is well‐established that endothelial cells exhibit heterogeneity. Indeed, in the pulmonary vasculature, pulmonary artery endothelial cells (PAECs) and pulmonary microvascular endothelial cells (PMVECs) exhibit a many differences, including differences in proliferation rate and growth inhibition. PMVECs have a greater proliferative potential than PAECS and do not exhibit contact inhibition of growth in culture. Additionally, PMVECs express higher levels of FK506‐binding protein 51 (FKBP51) than PAECs, a trait that confers resistance to the store‐operated calcium current, Isoc. Here, we asked whether FKBP51 affects endothelial cell phenotype. Pulmonary arterial hypertension is marked by endothelial dysfunction and vascular remodeling, and it has been suggested that phenotype switching via endothelial‐to‐mesenchymal transition or resident stem cells may contribute to disease progression. We investigated the role of FKBP51 in phenotype switching using an FKPB51‐overexpressing PAEC cell line. FKBP51‐overexpressing PAECs showed a two‐fold increase in doubling time compared to wild type PAECs. PAECs grow in islands, exhibiting a cobblestone appearance and contact‐dependent growth inhibition. On the other hand, FKBP51‐overexpressing PAECs have a PMVEC‐like phenotype, wherein cells take on a spindle‐like morphology when sub‐confluent and are not growth inhibited at confluence. In addition, FKBP51‐overexpressing PAECs show increased smooth muscle actin, an indicator of endothelial cell dedifferentiation, as compared to wild‐type PAECs. Taken together, these data suggest that FKBP51 may play an important role in phenotype switching in PAECs.

Support or Funding Information

American Heart Association #17AIREA33680155

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sympathetic Innervation Promotes Bone Marrow Homing of Specific CD8+ Effector Memory T Cells in Hypertension
Authors: Xiao Liang , Itani Hana A. , Foss Jason D. , Chen Wei , Harrison David G.
Published: June 2021

We have recently identified a critical role of hypertension‐specific effector memory T lymphocytes (TEM cells) in the blood pressure elevation and renal dysfunction caused by repeated hypertensive stimuli. Formed during an initial immune challenge, TEM cells reside in the bone marrow (BM) in a quiescent state for prolonged periods, and can be reactivated upon re‐exposure to the hypertensive stimulus. Hypertension is associated with increased sympathetic outflow. We therefore hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension‐specific TEM cells in the BM. We performed unilateral superior cervical ganglionectomy (SCGx) in wild‐type C57BL/6 mice, causing selectively sympathectomy of the forelimb on the surgical side. After recovery, mice received Ang II infusion for two weeks. To determine the changes of T cells in the BM that were specific to hypertension, 5×106 BM cells were isolated from either the SCGx or control limbs, loaded with proliferation marker CFSE, and co‐cultured with 0.5×106 splenic dendritic cells isolated from another Ang II‐infused mouse. We found 30% less CD8+ T cell proliferation in the SCGx BM compared to control side (1.9±0.2 vs. 2.8±0.1×104, p<0.001), but no difference in CD4+ T cells. To further study the effect of sympathetic nerves on BM T cell homing, 1×107 pan T cells were isolated from CD45.2+ wild‐type mice after Ang II infusion and adoptively transferred to CD45.1 mice that had previously undergone unilateral SCGx. Flow cytometry indicated that 7 days after transfer, 25% fewer CD8+ TEM cells from the hypertensive donors homed to the SCGx BM compared to the innervated BM (5.3±0.8 vs. 8.1±1.5 per 104 total T cells, p<0.05), suggesting that sympathetic nerves regulate CD8+ TEM homing in the bone marrow at baseline condition. To study enhanced local sympathetic nerve activity in BM observed in hypertension, excitatory DREADD (designed receptor exclusively activated by designed drug) was expressed in the SCG on one side of mice by microinjection of adeno‐associated viral vector. Two weeks later, the animals received pan‐T cells adoptively transferred from hypertensive donors, and the specific ligand clozapine‐N‐oxide for DREADD was given in drinking water for 7 days. In contrast to denervation, augmenting sympathetic nerve activity increased CD8+ TEM homing by ~50% compared to the baseline level (14.9±2.7 vs. 9.3±2.3 per 104 total T cells, p<0.01). These data define a novel role of sympathetic nerves in regulation of memory T cell trafficking in hypertension. Adrenergic blockade may be beneficial in disrupting survival of these injurious T cells, and thus might provide protection against repeated hypertensive stimuli known cause their reactivation.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Reduced bone marrow adrenergic receptor signaling is protective against weight gain and high fat‐induced hypertension
Authors: Ahmari Niousha , Yang Tao , Malphurs Wendi , Martyniuk Christopher J. , Zubcevic Jasenka
Published: June 2021

INTRODUCTION

Neurogenic hypertension (HTN) is characterized by activation of immune system (IS) in part via elevated sympathetic nerve activity (SNA) to the bone marrow (BM). We have previously shown that chronic increase in BM SNA is linked with heightened release of inflammatory cells (ICs) in rodent models of HTN. Conversely, specific genetic ablation of BM beta adrenergic receptors results in a decrease in circulating ICs and reduces blood pressure (BP). Considering the role of both elevated SNA and IS in obesity, we hypothesized that reduction of SNA effects on BM ICs will dampen the inflammation and BP responses to high fat diet.

METHODS

BM mouse chimera was created by reconstituting sub‐lethally irradiated male C57BL/6J mice (6 weeks old) with whole BM cells isolated from either the adrenergic beta 1 and beta 2 receptor knock out (Adrb1.b2KO) mice (Jax Labs stock#003810), to generate BM C57‐Adrb1.b2 KO chimera, or the wild type C57BL/6J mice, to generate BM C57‐C57 control chimera. Success of reconstitution was confirmed by PCR for beta 1 and 2 adrenergic receptors in circulating cells following a 3 month recovery. Mice were placed on either control (10 kcal fat) or high fat diet (60 kcal fat) ad libitum for two weeks. Weight and food intake were measured twice weekly in all mice. BP measurements were taken using tail cuff at baseline, and thereafter three times a week throughout the study. Visceral fat pads were collected and weighed at the conclusion of the study. Flow cytometry was used to quantify circulating ICs (T cells, neutrophils, macrophages) and endothelial progenitor cells at endpoint.

RESULTS

Both the BM C57‐C57 control chimera and BM C57‐Adrb1.b2 KO chimera mice had a statistically significant increase in total body weight following two weeks of high fat diet (by 5.33 g on average; P<0.05 vs control). However, only BM C57‐C57 control chimera mice had a significant increase in perirenal, epidymul, and retroperitoneal fat following high fat diet feeding (P<0.05). While mice on control diet had comparable BP values between the two groups, we observed a significantly elevated BP in BM C57‐C57 control chimera mice compared to the BM C57‐Adrb1.b2 KO chimera on high fat diet (mean systolic BP: 126.0 mmHg vs 105.7mmHg; p<0.05). However, no significant changes were observed in quantity of circulating CD4 T‐cells, macrophages, neutrophils or endothelial progenitors between the two mouse groups.

CONCLUSION

Reduced responsiveness of the BM hematopoietic cells to SNA is protective against high fat diet‐induced visceral fat gain and HTN, without significant changes in overall weight gain or circulating inflammatory cells.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Early blood pressure response to isometric exercise is attenuated in obese individuals who have undergone bariatric surgery
Authors: Guo Winston , Joyner Michael J. , Curry Timothy B. , Limberg Jacqueline K.
Published: June 2021

Objective

Blood pressure (BP) reactivity to stress is predictive of the development of cardiovascular disease. Cardiovascular reactivity is attenuated in individuals after bariatric surgery; however, the underlying mechanisms are not completely understood. We hypothesized the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery when compared to obese adults and the reliance on total peripheral resistance (TPR) would be attenuated.

Methods

Twenty‐six individuals [7 non‐obese (28±3 yrs, 23±1 kg/m2), 11 obese (33±2 yrs, 39±1 kg/m2), 8 post‐bariatric surgery (35±2 yrs, 29±1 kg/m2)] completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30‐s of exercise.

Results

Compared to non‐obese controls, obese adults exhibited a slower initial rise in BP (9.3± 3.9 vs 21.7±2.5 s) and higher peak BP change (Δ6.7±2.1 vs Δ11.9±2.1 mmHg) at the onset of isometric handgrip exercise (p<0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery (14.0±4.1 s, Δ5.6±1.3 mmHg) and non‐obese controls (p>0.05). Non‐obese controls exhibited an exercise‐mediated increase in CO whereas obese adults increased TPR (p<0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery (p>0.05). Low cardiac baroreflex sensitivity (BRS) and heart rate variability (HRV: SDNN, standard deviation of normal to normal R‐R intervals) at rest were related to smaller increases in CO (BRS: R=0.47, p<0.01; SDNN: R=0.57, p<0.01) and greater increases in TPR (BRS: R=−0.49, p=0.01; SDNN: R=−0.60, p<0.01) during exercise.

Conclusions

In contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at the onset of isometric handgrip exercise. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest bariatric surgery attenuates BP reactivity to physical stress via improvements in the time‐course of hemodynamic responses and reflex autonomic adjustments.

Support or Funding Information

NIH HL130339, NIH HL083947, NIH DK82424, NIH UL1 RR024150, Mayo Clinic Department of Anesthesiology, Mayo Foundation for Medical Education and Research

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leptin‐mediated Sympatho‐excitation in Obese Rats: Role for Astrocyte‐Neuron Crosstalk in the Arcuate Nucleus
Authors: Liu Xuefei , Li Yulong , Patel Kaushik P. , Zheng Hong
Published: June 2021

Accumulated evidence indicates that enhanced sympathetic activation is associated with obesity. Hypothalamic leptin‐mediated signaling may contribute to the exaggerated sympatho‐excitation in obesity. The present study was conducted to investigate “neuron‐astrocyte” interactions regulating leptin signaling within the arcuate nucleus (ARCN) of hypothalamus in obese rats. High‐fat diet (42% fat for 12 weeks) induced hyperlipidemia and hyperleptinemia in Sprague Dawley rats. In anaesthetized condition, microinjections of leptin (5ng~100ng) and N‐methyl‐D‐aspartate (NMDA 50–200pmol) into the ARCN induced increases in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in both control and obese rats. Pre‐inhibition of astrocytes with astrocytic metabolic inhibitor fluorocitrate reduced leptin‐induced, but not NMDA‐induced RSNA and MAP within the ARCN. In the ARCN, leptin/leptin receptor is localized in both neurons and astrocytes. In obese rats, leptin and leptin receptor were increased in the ARCN, particularly increased more in the astrocytes than in the neurons. Furthermore, we found that the expressions of glutamate transporter GLT1 and excitatory amino acid transporter‐2 (EAAT‐2) which are major glutamate transporters expressed predominantly in astrocytes were decreased within the ARCN in obese rats. Consistent with these in‐vivo observations, in cultured astrocytic C6 cells, GLT1 and EAAT‐2 levels decreased with leptin (100 ng/ml) treatment for 24 hours. Taken together, these results suggest leptin signaling via neuron‐astrocytes interactions in the ARCN may contribute to the exaggerated sympatho‐excitation observed in obese rats. This effect maybe mediated by the action of leptin regulating glutamate transporters in the astrocytes within the ARCN of the hypothalamus.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Environmental Enrichment Reverses Chronic Stress‐Induced Brain‐Gut Axis Dysfunction
Authors: Love James , Johnson Anthony , Ligon Casey , Meerveld Beverley Greenwood‐Van
Published: June 2021

Stress‐induced visceral hyperalgesia is a contributing factor in irritable bowel syndrome (IBS), a highly prevalent brain‐gut disorder characterized by chronic visceral pain. Previously we showed that repetitive daily exposure to a water avoidance stressor (WAS) for 1 hr/day for 7 days induced visceral and somatic hyperalgesia in a rodent model. A positive environment enrichment (EE) is known to have a critical role in brain development and stress reactivity, however it is unknown whether EE is capable of reversing stress‐induced viscero‐somatic hypersensitivity.

Methods

Experiments were performed on male F344 rats that were housed in either standard housing (SH) or in large cages filled with toys and food treats for EE. The effect of EE (7–14 days) before and/or during the WAS or sham stress (SHAM) induced visceral and somatic hypersensitivity was investigated (n=4/group). Visceral sensitivity was assessed via a visceromotor response (VMR) to graded pressure (0–60 mmHg) of isobaric colorectal distension (CRD). Somatic sensitivity was measured via von Frey filaments applied to the hind paw. Results were analyzed with one‐ or two‐way ANOVA with a Bonferroni's correction.

Results

Compared to male rats placed in SH, we found that EE for 14 days before and during the 7 days of WAS produced a significant attenuation in visceral (60 mmHg, WAS+EE=19.8±4.0 vs. WAS+SH=28.5±4.1 abdominal contractions, p<0.05) and somatic hypersensitivity (WAS+EE=85.7±7.4 vs. WAS+SH=65.6±4.5 g withdrawal threshold, p<0.01). In a similar fashion, rats housed with EE for only 7 days before and during the WAS procedure also demonstrated a significant reduction in visceral hypersensitivity and somatic allodynia. However, when rats were not pre‐exposed to EE and only housed in an EE during the time of the WAS procedure, there was no significant inhibition of WAS‐induced visceral hypersensitivity (60mmHg, WAS+EE=27.7±11.0 abdominal contractions) or somatic allodynia (WAS+EE=59.3±5.1 g).

Summary and Conclusions

Our data reveal that pre‐exposure of adult animals to short‐term EE prevents visceral and somatic hypersensitivity induced by chronic repetitive stress. Future experiments are designed to understand the basic underlying molecular mechanisms responsible for the positive effects of EE on stress‐induced visceral and somatic hyperalgesia and its implications in the treatment of brain‐gut axis dysfunction.

Support or Funding Information

Dr. Greenwood‐Van Meerveld would like to acknowledge the funding provided by her Department of Veterans Affairs Merit Grant – I01BX002188. Dr. Greenwood‐Van Meerveld is the recipient of a Senior Research Career Scientist award (1IK6BX003610) from the Department of Veterans Affairs.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Visceral Organ Cross‐Sensitization in a Rodent Model of Early Life Stress
Authors: May Jeffery , Mohammadi Ehsan , Johnson Anthony C. , Meerveld Beverly Greenwood‐Van
Published: June 2021

INTRODUCTION AND OBJECTIVE

Bladder pain syndrome (BPS) and irritable bowel syndrome (IBS) exhibit a high comorbidity, show a female predominance, and patients often report a history of early life stress (ELS). However, whether ELS serves as a risk factor for visceral organ cross‐sensitization remains to be determined. Our previous work suggests that multi‐organ visceral hypersensitivity results from visceral organ crosstalk. In this study, we test the novel hypothesis that ELS induces chronic visceral pain in adults through bladder‐colon crosstalk.

METHODS

Neonatal female Long Evans rats were exposed to an odor attachment learning model of ELS produced by classical conditioning. On postnatal (PN) days 8 to 12 neonatal female rats (n=27) were separated into: Group 1: odor with an unpaired shock [Unpredictable ELS], Group 2: odor only. In adulthood (PN 90) dilute protamine sulfate (PS) (1mg/ml) was infused into the bladder via intravesical infusion. Colon sensitivity was assessed 24 hr. post PS in freely moving animals as a visceromotor response (VMR) to graded pressures (0–60mmHg) of isobaric colorectal distension and quantified as the number of abdominal contractions over 10 min. Rats receiving no PS infusion served as controls.

RESULTS

In adults PS infusion into the bladder significantly increased colonic sensitivity in all groups (VMR at 60mmHg: Odor Only=21.4±1.7 (n=5) vs Odor Only plus PS=36.0±1.8 (n=10) [p<0.0001], Unpredictable ELS=38.7±3.6 (n=6) vs Unpredictable ELS plus PS=52.7±1.7 (n=6) [p<0.0001] abdominal contractions). The crosstalk‐induced increase in colonic hypersensitivity was similar between the odor only and unpredictable ELS groups (ΔVMR at 60mmHg (plus PS – no PS): Odor Only=14.6±1.7 vs Unpredictable ELS=14.0±3.6 [p=0.90]).

SUMMARY & CONCLUSIONS

Our data revealed that in adulthood intravesical infusion of PS into the bladder in female rats previously exposed to ELS as neonates induces colonic hyperalgesia, however the magnitude of the PS‐induced colonic hyperalgesia did not differ between groups. These findings, in a rodent model, suggest that unpredictable ELS does not augment acute visceral organ cross sensitization in adulthood.

Support or Funding Information

In‐house funding from the Greenwood‐Van Meerveld lab was used to support this project.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inulin/FOS‐rich diet alters gut microbiota, brain activity and cardiovascular responses in the SHR
Authors: Silva Carla Grazielle Bueno , Yang Tao , Malphurs Wendi L. , Magee Kacy L. , Larkin Riley M. , Febo Marcelo , Vickroy Thomas W. , Zubcevic Jasenka
Published: June 2021

It is well established that hypertension is associated with autonomic dysfunction and gut dysbiosis. Here, we show that chronic inulin/FOS‐rich diet alters gut microbiota, promotes autonomic dysfunction, and increases BP in conscious unrestrained spontaneously hypertensive rat (SHR), as well as the SHR submitted to restraint stress. These alterations were accompanied by activation of cardioregulatory brain regions, namely the paraventricular nucleus (PVN) of hypothalamus and solitary tract nucleus (NTS), as measured by manganese‐enhanced magnetic resonance imaging (MEMRI). BP was also significantly increased in the inulin/FOS diet‐fed Wistar‐Kyoto (WKY) rat submitted to restraint stress, albeit to a lesser extent.

Methods

Male 4 weeks old WKY and SHR were placed on either the inulin/fructooligosaccharides (FOS)‐rich diet (fiber, n=6), or its calorie‐matched control diet (ctl, n=6) (Research Diets, Inc.) for 14 weeks. BP was measured weekly by tail cuff and telemetry, and during 20 minutes of restraint stress. Spectral analysis of BP waveform signal was performed to derive autonomic variables. MEMRI was performed in SHR at tenth week on diet.

Results

Inulin/FOS‐rich diet caused significant shifts in gut bacterial profiles in WKY and SHR as an increase in Bifidobacterium population (WKY: 0.006624 ± 0.0018 vs. 0.4989 ± 0.1745 arbitrary unit; p=0.0073, n=6. SHR: 0.03099 ± 0.0127 vs. 0.2134 ± 0.0656 arbitrary unit; p=0.0258, n=6). We observed no change in BP in conscious unrestrained WKY; however, conscious unrestrained SHR fed with inulin/FOS diet had significantly higher mean BP compared to control (163.8 ± 1.6 vs. 169.6 ± 1.3 mmHg; p=0.0083, n=6). Restraint stress produced a small but significant increase in BP in inulin/FOS‐fed WKY compared to control (104.5 ± 7.45 vs. 116.3 ± 3.19 mmHg; p=0.0411, n=6). This effect was more pronounced in the SHR on inulin/FOS compared to control diet (189.6 ± 2.1 vs. 198.9 ± 1.9 mmHg; p=0.0024, n=6). These responses were associated with a trend in increase in LF/HF (vasovagal) balance in the diet‐fed WKY (1.99 ± 1.43 vs. 3.04 ± 1.46; p=0.09, n=6), and with significant increase in LF/HF in the diet‐fed SHR (6.49 ± 0.47 vs. 8.16 ± 0.59, p=0.0306, n=6). MEMRI showed increased activation of the PVN (−0.6514 ± 0.07 vs 0.05026 ± 0.06 % of baseline; p=0.0018, n=3) and NTS (0.1194 ± 0.05 vs. 0.3817 ± 0.09 % of baseline; p=0.0409, n=3) in diet‐fed SHR.

Conclusion

Gut microbiota plays an important role in brain‐gut communication in hypertension. This pathway may present a novel therapeutic target for treatment of this condition.

Support or Funding Information

FAPESP : Fundação de Amparo à Pesquisa do Estado de São Paulo

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Western versus Omega‐3 Based Diets Differentially Alter Key Brain Fatty Acid Transport Genes
Authors: Umbaugh David S. , Schaller Megan L. , Harris Matthew P. , Wooten Joshua S. , Sandoval Karin E. , Witt Ken A.
Published: June 2021

The Western high‐fat diet is associated with poor health outcomes, while omega‐3 fatty acids supplementation has shown to mitigate metabolic imbalances seen with the Western diet. Growing evidence shows diet impacts cerebrovascular and brain health. Understanding of how the percentage and type of fat in the diet affects brain and microvascular expression of fatty acid transport genes remains limited.

PURPOSE

To elucidate the dietary impact of fat type (lard vs. fish oil) and percentage of fat (10% vs 41%) on metabolic parameters and expression of key genes associated with transport and actions of fatty acids in the brain and microvasculature.

METHODS

8‐week male C57Bl/6 mice (n = 12/group) were randomized to one of four treatment groups: 10% kcal lard,10% kcal fish (menhaden) oil 41% kcal lard or 41% kcal fish oil ad libitum for 32 weeks. Total plasma cholesterol, LDL, HOMA‐IR, glucose, and triglycerides were measured at the conclusion of the study. Cortical (cerebral cortex) and subcortical (hippocampus, amygdala, thalamus, caudate) brain tissues were harvested and mRNA expression (Mfsd2a, Cd36, ApoE, Abca1, Ppara, Pparg) was measured via RT‐qPCR relative to the 10% lard diet. Mfsd2a protein expression was assessed via Western blot.

RESULTS

Mean total cholesterol, LDL, glucose and HOMA‐IR significantly differed with the type of fat, the percentage of fat, and their interaction. The mean LDL, total cholesterol, glucose and HOMA‐IR were significantly higher in mice receiving 41% lard compared to mice receiving other diets. Mean cortical Mfsd2a protein expression significantly differed with the percentage of fat and the interaction between the type and percentage of fat. Mean Mfsd2a protein expression was significantly higher in all other diet groups compared to 10% lard. Mean cortical Mfsd2a mRNA expression differed with the type of fat. Mice receiving fish oil had higher‐fold Mfsd2a mRNA expression compared to those receiving lard. Mean cortical Pparg mRNA expression significantly differed with the type and percentage of fat. Mice receiving fish oil or 41% fat had higher‐fold Pparg expression compared to mice receiving lard or 10% fat, respectively.

CONCLUSIONS

Findings showed that the type and percentage of fat could play a critical role in the metabolic profile and expression of genes involved in the transport or action of fatty acids in the cerebrovasculature and/or brain.

Support or Funding Information

This work was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (Grant: R21NS090282).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.