bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced vestibular function in veterans is associated with worse cerebral autoregulation (1068.15)
Authors: Serrador Jorge , Acosta Amanda , Ghobreal Bemin , Blatt Melissa 
Published: June 2021

Recent data has demonstrated that veterans returning from Iraq and Afghanistan have increased incidence of mild traumatic brain injury (mTBI) as well as impaired vestibular function. The objective of this work is to determine if reduced vestibular function is associated with impaired cerebral autoregulation. To asses vestibular function we measured ocular torsion, rotation of the eye within the socket during roll tilt. This vestibular ocular reflex provides us an index of otolith function. To assess cerebral autoregulation we had veterans perform three sit to stand maneuvers while measuring beat‐by‐beat blood pressure, cerebral flow velocity in the middle (MCA) and anterior cerebral artery (ACA) and end tidal CO2. 11 Veterans completed both vestibular and cerebral autoregulation assessments. Ocular torsion ranged from 0.03 to 0.32 deg torsion per deg head tilt (Mean 0.14). Ocular torsion was correlated to autoregulatory index (ARI) in the MCA (R2=0.115, P=0.058) and the ACA (R2=0.212, P=0.018), with lower ocular torsion having reduced ARI. Defining low ocular torsion using a mean split, we found significantly lower ARI values in both MCA (Low 3.4±0.3 vs High 4.7±0.5, P=0.014) and ACA (3.3±0.3 vs 5.0±0.5, P=0.003). These data suggest that impaired vestibular function in these veterans is associated with worse cerebral autoregulation. One possible explanation is that veterans with reduced torsion also have mTBI and thus both the reduced vestibular function and the impaired autoregulation are a consequence of mTBI. Further work is needed to examine the connection between mTBI, vestibular function and cerebral autoregulation.Grant Funding Source: Supported by Dept of Veteran Affairs and NIH R21 DC009900
Lack of a sex difference in leptin‐mediated regulation of appetite, cardiovascular function and glucose homeostasis (1083.5)
Authors: da Silva Alexandre , Pinkerton Mark , Spradley Frank , Palei Ana , do Carmo Jussara 
Published: June 2021

Previous studies using male rodents have shown that the adipocyte‐derived hormone leptin acts in the brain to regulate cardiovascular function and energy homeostasis noted by modulation of appetite and energy expenditure and normalization of diabetes‐induced elevations in glucose levels. Because it is uncertain if leptin acts similarly in females, the aim of our study was to examine sex differences in leptin’s actions on blood pressure (BP), heart rate (HR), appetite, and glucose homeostasis. Female Sprague‐Dawley rats (n=6) and male controls (n=5) were instrumented with intracerebroventricular (ICV) cannulas in the lateral ventricle for continuous 7‐day infusion of leptin (15 μg/day) and telemetry probes for measurement of BP and HR 24‐hr/day. At baseline, female rats had significantly lower MAP (96±3 vs. 104±4 mmHg, p<0.05) but higher HR (375±5 vs. 335±5 bpm, p<0.05) compared to males but, following leptin treatment, we observed similar rises in BP (~3 mmHg) and HR (~25 bpm) in both sexes. Females had significantly reduced body weight (BW, 283±2 vs. 417±7 g, p<0.05) and lower caloric intake (162±20 vs. 192±9 kcal/kg of BW, p<0.05) compared to males, and leptin infusion reduced BW (‐10%) and caloric intake (‐62%) in both sexes alike. Also, in females and males, leptin infusion significantly reduced, to a similar extent, both fasting insulin (1.9±0.5 vs. 0.6±0.3 and 1.9±0.2 vs. 0.3±0.1 ng/ml, respectively) and blood glucose levels (100±6 vs. 75±6 and 80±4 vs. 73±5 mg/dl, respectively). In female rats with streptozotocin‐induced diabetes (n=5), chronic ICV leptin treatment for 7‐days also completely normalized the elevated glucose levels (315±33 vs. 83±13 mg/dl, p<0.05). These results show that the effects of leptin on cardiovascular function, glucose regulation and energy homeostasis are similar in male and female rats. Therefore, our results provide no evidence of a sex difference in leptin’s cardiovascular or metabolic actions. (NHLBI‐PO1HL51971, NIGMS P20GM104357, AHA‐SDG5680016)Grant Funding Source: NIH: NHLBI‐PO1HL51971 and NIGMS P20GM104357; AHA: SDG5680016
Role of Src homology 2 domain‐containing protein B in the regulation of GFR and renal afferent arteriole responsiveness (1088.12)
Authors: Gao Xiang , Sällström Johan , Ma Zufu , Welsh Michael , Persson A. Erik 
Published: June 2021

BACKGROUND: Src homology 2 domain‐containing protein B (Shb) is an adapter protein which regulates several signal transduction cascades and endothelial cell functions. We used Shb‐knockout (Shb‐/‐) and wild‐type (Shb+/+) mice to investigate the role of Shb in regulating glomerular filtration rate (GFR), vascular resistance and tubuloglomerular feedback.METHODS: GFR was measured in conscious Shb‐/‐ and Shb+/+ mice using FITC‐inulin. Isotonic contractions were measured in isolated and perfused renal afferent arterioles from Shb‐/‐ and Shb+/+ mice. Concentration responses to Ang II (10‐12 to 10‐6M; 2 minutes each) doses, low‐dose Ado (10‐8 mol/l; 15 min) alone or Nω‐nitro‐l‐arginine methyl ester (L‐NAME; 10‐4 mol/l; 15 min) alone, as well as Ado (10‐8 mol/l) or nitric oxide (NO) synthase inhibitor L‐NAME (10‐4 mol/l) in combination with cumulative application of Ang II (10‐12 to 10‐6 mol/l; 2 minutes each) were studied in both genotypes.RESULTS: There was a significantly increased GFR (371 ± 12 µl/min, n=11) in Shb‐/‐ comparing to Shb+/+ (321 ± 11 µl/min, n=8) mice. The maximal arteriolar contraction to Ang II was remarkably larger in Shb‐/‐ (87 %, n=8) than in Shb+/+ (54 %, n=8) mice. Low‐dose Ado contracted afferent arterioles in both genotypes (6% in Shb‐/‐ and 7% in Shb+/+). Ado significantly enhanced Ang II constriction in afferent arterioles in both genotypes (to 93% in Shb‐/‐ and to 72 % in Shb+/+). L‐NAME reduced arteriolar diameters significantly more in Shb‐/‐ (14 %, n=7) than in wild types (9 %, n=7) and remarkably augmented ANG II responses in both genotypes. L‐NAME with Ang II almost fully constricted renal afferent arterioles in Shb‐/‐ (98 %), while contracted 64% in Shb+/+ mice.CONCLUSION: The absence of Shb markedly increases GFR. Both low‐dose adenosine and L‐NAME treatments significantly augment Ang II arteriolar constriction effectiveness, which indicates Ado‐Ang II and NO‐Ang II interactions in both Shb‐/‐ and Shb+/+ mice. The underlying mechanisms remain to be resolved.
Nucleic acid binding of annexin A2 is regulated through angiotensin II/AT1 signaling in kidneys of hypertensive rats (1088.2)
Authors: Hultström Michael , Paliege Alexander , Skogstrand Trude , Fähling Michael 
Published: June 2021

The aim was to identify new targets that regulate gene expression at the post‐transcriptional level in hypertension. Heparin affinity chromatography was applied to enrich putative nucleic acid‐binding proteins from kidneys of 2K1C hypertensive rats. A 0.2mm silver clip was used to induce hypertension (sham: 109±8 mmHg, 2K1C: 146±6 mmHg, P<0.05). We found a 36 kDa protein that showed an increased affinity to the nucleic acid mimetic in the 2K1C model. This factor was identified by LCMSMS and western blotting as Annexin A2 (ANXA2), a RNA‐binding protein known to influence mRNA stability and translation. Immunofluorescence staining revealed widespread distribution of ANXA2 throughout the kidney with high levels in endothelial cells, the cells of the Bowman capsule and in the medullary collecting ducts. Infusion of angiotensin II (AngII) reproduced our findings in the 2K1C animals and the AT1a blocker Losartan abolished the effect on Annexin A2. Strikingly, we observed no change in total Annexin A2 protein levels or localization, suggesting that post‐translational modification modulates Annexin A2 function via ANGII/AT1a signalling. In conclusion, AngII regulates the nucleic acid binding activity of Annexin A2 in the kidneys of rats with hypertension and, thus, may be an important regulator of gene expression in this setting.Grant Funding Source: Supported by Lars Hierta Foundation, Magnus Bergvall Foundation, Swedish Society for Medical Researc
G protein‐coupled receptor expression and function in pulmonary artery smooth muscle cells: new targets in pulmonary arterial hypertension (1090.3)
Authors: McDonald Daniel , Aroonsakool Nakon , Kwon Ohmin , Insel Paul , Murray Fiona 
Published: June 2021

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, in part due to increased proliferation of pulmonary artery smooth muscle cells (PASMC). Since 3’5’‐cyclic adenosine monophosphate (cAMP) decreases proliferation of PASMC, G protein‐coupled receptors (GPCRs) that couple to Gαs or Gαi are attractive targets for the treatment of PAH. We used a real‐time PCR GPCR array to identify and quantify the GPCRs expressed by PASMC isolated from normal subjects and from patients with PAH. We found that human PASMC express >135 GPCRs, at least 60 of which regulate cAMP formation. GPCR expression correlates with function: for Gαs‐coupled GPCRs with formation of cAMP and inhibition of cell proliferation, thus documenting that the GPCR array identifies physiologically relevant GPCRs. PAH‐PASMC (both from idiopathic and secondary PAH patients) have an increase (>2‐fold) in the expression of 41 GPCRs compared to control‐PASMC, including multiple GPCRs that link to Gαs or Gαi. In addition, PAH‐PASMC have a higher expression of GPCRs that preferentially couple to Gαq/11 or to Gα12/13. Taken together these data provide evidence that a GPCRomic approach can identify GPCRs that may contribute to the physiology of PASMC and that may be new druggable targets for PAH, a disease for which no currently optimal therapies exist.Grant Funding Source: NIH
Overexpression of HSP72 protects against mechanical ventilation‐induced mitochondrial dysfunction and apoptotic signaling in the diaphragm (1091.1)
Authors: Smuder Ashley , Sollanek Kurt , Min Kisuk , Kwon Oh Sung , Nelson W , Powers Scott 
Published: June 2021

Mechanical ventilation (MV) is a life‐saving measure for patients in respiratory failure. However, prolonged MV results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, developing effective countermeasures to protect against MV‐induced diaphragm weakness is important. In this regard, HSP72 overexpression has been demonstrated to protect against skeletal muscle dysfunction during a variety of conditions (i.e. hindlimb immobilization and cancer cachexia). Therefore, the current study tested the hypothesis that HSP72 overexpression in the diaphragm would protect against MV‐induced diaphragm dysfunction. Cause and effect was determined using a novel technique to overexpress HSP72 in the rat diaphragm via an adeno‐associated virus vector delivered directly to the diaphragm. Our results demonstrate that 12 hours of MV results in impaired mitochondrial function and a significant increase in mitochondrial ROS release, which leads to caspase‐3 activation and increased apoptosis within the diaphragm. Overexpression of HSP72 in the diaphragm protected against these alterations and inhibited MV‐induced apoptotic signaling. Therefore, HSP72 overexpression in the diaphragm may have therapeutic potential to combat MV‐induced diaphragm weakness.Grant Funding Source: This work was supported by NIH R01 AR064189 awarded to SK Powers.
Novel signaling function of hCLCA1 in airway macrophages activation (1095.2)
Authors: Ching John , Loewen Matthew 
Published: June 2021

The CLCA gene family produces both secreted and membrane‐associated proteins that modulate ion‐channel function, drive mucus production and have a poorly understood pleiotropic effect on airway inflammation. In airway inflammation, the primary up‐regulated human CLCA ortholog is hCLCA1. Here we show that secreted hCLCA1 is able to activate macrophages, inducing them to express cytokines and to undertake a pivotal role in airway inflammation. Conditioned media collected from HEK293 cells heterologously expressing hCLCA1 increased the expression of pro‐inflammatory cytokines (IL‐1β, IL‐6, TNF‐α, and IL‐8) in U‐937 monocyte‐macrophage cell line. Similar pro‐inflammatory response was achieved in primary porcine alveolar macrophages activated with hCLCA1 conditioned media, showing that the effect was not cell line dependent. Immuno‐purified hCLCA1 at physiologically relevant concentration of ~100 pg/mL was also able to elicit pro‐inflammatory response in macrophages. These findings demonstrating that secreted hCLCA1 is able to function as a signaling molecule and to regulate cytokine expression in macrophages.Grant Funding Source: NSERC
Characterization of the immune response in male and female mice following lipopolysaccharide‐induced systemic inflammation (1096.10)
Authors: Bubalo Nina , Nguyen Peter , Nguyen Tuan , Abramson Tzvia , Wilkinson Katherine 
Published: June 2021

Intraperitoneal injection of lipopolysaccharide (LPS) is a common method to induce systemic inflammation, but there is wide variability in the doses given and no standardized measure of inflammatory level. We characterized the inflammatory response in adult male and female C57BL/6 mice following 3 LPS exposure protocols by measuring body weight changes, spleen weight and immune cell composition in the blood using flow cytometry. Mice were injected twice a week for 1 month with either a 200 μL dose of saline or a low dose of LPS (7.5 x 10^4 EU/kg). Half the animals in each condition were injected with a high dose of LPS (7.5 X 10^5 EU/kg) the day before sacrifice. Acute exposure to a high dose of LPS caused a 10.6% decrease in body weight overnight and no significant change in spleen weight. White blood cell and lymphocyte counts decreased and toll‐like receptor 4 (TLR4) positive macrophage count increased for both males and females. Exposure to 1 month of low LPS caused no change in the immune cell composition in the blood and body weight, but spleen weights were significantly increased compared to saline animals. 1 month of low LPS followed by high LPS caused an even greater increase in spleen weight than the 1 month low LPS condition, but no other changes. In summary, all 3 LPS exposure protocols led to evidence of an immune response in both sexes, but body weight and blood immune cell composition normalized following chronic low LPS exposure.Grant Funding Source: Supported by a CSUPERB New Investigator Award (KAW)
Effects of muscle specific VEGF loss on muscle hypertrophy and function induced by functional overload in mice (1102.6)
Authors: Huey Kimberly , Delavar Hamid , Breen Ellen 
Published: June 2021

Functional overload (FO) stimulates muscle growth and increases strength and endurance. Vascular endothelial growth factor (VEGF) is essential for exercise‐induced angiogenesis. We hypothesized VEGF expressed by skeletal myofibers is critical for muscle growth and improvements in force production and fatigue resistance. To test this hypothesis, adult mice with conditional skeletal myofiber specific VEGF gene deletion (skmVEGF‐/‐) and wild type (WT) littermates underwent functional overload (FO) of the plantaris (removal of gastrocnemius and soleus) or sham surgery. In vivo plantaris isometric force and fatigue resistance (% of maximal force after 10 contractions) were measured 7 or 14d after FO or sham surgery with a dual mode foot plate system in anesthetized skmVEGF‐/‐ or WT mice. Mass increased ~ 35% in both 14d‐FO groups compared to sham (p<0.01). In WT mice subjected to FO, maximal isometric force was unchanged at 7d and increased at 14d (sham, 0.37±0.03; FO, 0.46±0.04 g/mg body mass, p<0.05). In skmVEGF‐/‐ mice, FO was associated with a decrease in maximal force after 7d (sham, 0.39±0.0; FO, 0.23±0.03 g/mg body mass, p<0.05) and 14d (sham, 0.39±0.03; FO, 0.27±0.04 g/mg body mass, p<0.05). Fatigue resistance was not different between groups at 7d. After 14d of FO, fatigue resistance increased from 58±3%‐sham to 73±2%‐FO of maximal force in WT mice (p<0.05) and was unchanged in skmVEGF‐/‐ mice. These data suggest that VEGF‐dependent functions are essential for improving muscle strength and fatigue resistance, independent of muscle growth, in response to a hypertrophic stimulus.Grant Funding Source: Supported by NIH R15AR060469
Radiation combined with hind‐limb suspension affects physiological parameters in rats (1103.7)
Authors: Chowdhury Parimal , Long Ashley , Akel Nisreen , Gaddy Dana , Griffin Robert , Bailey Lauren , Dobretsov Maxim 
Published: June 2021

This study examines acute and degenerative tissue responses to space‐like radiation doses in a rodent model of simulated microgravity. Three groups of rats, control (CON), irradiated (IR) and irradiated plus suspended (IR+HLS) were maintained for two weeks. IR and IR+HLS groups were exposed to radiation dose of 10GY. Body weights, soleus muscle weights, malondialdehyde (MDA), insulin/glucose levels, pressure‐pain threshold (PPT), grip force and heat pain were measured. CON gained weight faster than IR or IR+HLS. HLS but not IR resulted in soleus muscle atrophy. Bone mineral density in the proximal tibia was compromised by HLS and decreased by IR+HLS. Random plasma glucose levels were not affected by IR or IR+HLS. IR increased plasma insulin levels. PPT was increased in CON, remains unchanged in IR and decreased in (IR+HLS). MDA in plasma or in soleus muscle remain almost unchanged in CON, IR and (IR HLS) rats. However, IR significantly increased soleus muscle Cyt / Arg ratio over CON. Grip force, and/or low back pain did not differ between CON, IR and IR+HLS groups. No effects of irradiation were seen in heat pain threshold measurements. IR eliminated “hypoalgesia” and (IR+HLS) produced hyperalgesia. Moreover, IR exacerbated the HLS‐induced bone loss in the proximal tibia. These data suggest that radiation induces major physiological changes and these changes are exacerbated by exposure to HLS.Grant Funding Source: Arkansas Space Grant Consortium
Effect of passive heating on arterial compliance in smokers vs. non‐smokers (1106.1)
Authors: Moyen Nicole , Ganio Matthew , Burchfield Jenna , Tucker Matthew , Gonzalez Melina , Dougherty Erin , Robinson Forrest , Ridings Christian , Veilleux Jennifer 
Published: June 2021

An inverse relationship exists between baseline arterial compliance (AC) and changes with passive heating in non‐smokers, yet it is unknown if this relationship exists in smokers. Purpose: To examine the effects of passive heating on AC in chronic smokers (S) vs. non‐smokers (NonS). Methods: 13 S and 13 NonS (27.2 ± 7.9 y; 78.8 ± 15.4 kg; 177.6 ± 6.7 cm) were passively heated until core temperature (TC) increased 1.5 °C from baseline. At baseline and each 0.5 °C TC increase, AC was assessed peripherally and centrally using an ultrasound measuring pulse wave velocity (pPWV and cPWV, respectively). Results: Independent of group, cPWV significantly increased (p < 0.005) from baseline (grand mean: 526.7 ± 81.7 cm/s) to 1.5 °C (579.7 ± 69.8 cm/s). Regardless of group, pPWV did not change with heating (grand mean: baseline = 691.9 ± 92.9; 1.5 °C = 691.9 ± 79.5 cm/s; p > 0.05). Changes in cPWV and pPWV with heating negatively correlated (p < 0.05) with baseline PWV in S (cPWV: r = ‐0.59; pPWV: r = ‐0.62) and NonS (cPWV: r = ‐0.45; pPWV: r = ‐0.77). However, the magnitude of these relationships did not differ between S and NonS, either centrally or peripherally (p > 0.05). Conclusion: Passive heating to a 1.5 °C TC increase similarly affected AC in S and NonS. Inverse relationships between baseline PWV and changes in PWV with heating suggest the effect of heat on AC depends on baseline normothermic compliance.Grant Funding Source: Supported by: Arkansas Biosciences Institute, Arkansas Tobacco Settlement Proceeds Act of 2000
A role for the circadian clock protein Per1 in the regulation of NHE3 and SGLT1 in human proximal tubule cells (1109.4)
Authors: Richards Jacob , All Sean , Cheng Kit‐Yan , Gumz Michelle 
Published: June 2021

Mounting evidence has demonstrated that renal function and blood pressure undergo circadian oscillations. Our lab has previously demonstrated that the circadian clock protein Per1 regulates multiple genes involved in sodium reabsorption in the renal collecting duct, but other parts of the nephron have not been investigated. The proximal tubule is responsible for a majority of sodium reabsorption. The goal of this study was to determine if NHE3 and SGLT1 were regulated by the circadian clock protein Per1. Pharmacological blockade of nuclear Per1 entry resulted in decreased mRNA expression of SGLT1 and NHE3, but not SGLT2 in the renal cortex of mice. These findings were confirmed using Per1 siRNA and pharmacological blockade of Per1 nuclear entry in HK‐2 human proximal tubule cells. Transcriptional regulation was demonstrated by measuring short‐lived hnRNA. Chromatin‐immunoprecipitation experiments demonstrated the interaction of Per1 and CLOCK with the promoters of NHE3 and SGLT1, an effect that was reduced by blockade of Per1 nuclear entry. Importantly, both membrane and intracellular protein levels of NHE3 and SGLT1 were decreased following blockade of nuclear Per1 entry. These data demonstrate a role for Per1 in the transcriptional regulation of NHE3 and SGLT1 in proximal tubule cells.Grant Funding Source: Supported by NIH, ASN and AHA
An emerging link between the negative EGFR feedback regulator Mig6 and hepatic glucose production (1115.5)
Authors: Lutkewitte Andrew 
Published: June 2021

Hepatic glucose production (HGP) from either glycogenolysis or de novo gluconeogenesis requires the hydrolytic cleavage of glucose‐6‐phosphate to glucose and inorganic phosphate by the glucose‐6‐phosphatase catalytic subunit (G6Pase). G6Pase is induced during fasting, type 2 diabetes (T2D), and endoplasmic reticulum (ER) stress to promote HGP. In contrast, G6Pase can be suppressed by hormonal signals including activation of the epidermal growth factor receptor (EGFR). As a negative regulator of EGFR, Mitogen‐inducible gene 6 (Mig6) could be a novel target for modulating HGP. Thus, we hypothesized that Mig6 induction increases HGP by inhibiting EGFR‐mediated suppression of G6Pase. Using C57Bl/6 mice and HepG2 cells, we determined that Mig6, like G6Pase, is induced during fasting, diabetes, and ER stress. To further study this regulation, we generated liver‐specific Mig6 knockout (LKO) mice by crossing Mig6flox/flox mice with albumin‐Cre transgenic mice. Compared to wild‐type littermates, LKO mice had a 2‐fold increase in liver weight and an increase in total liver glycogen. Moreover, LKO had reduced G6Pase expression with no change in glucokinase or PEPCK gene expression, suggesting that EGFR signaling restrains G6Pase expression in vivo. We conclude that similar to G6Pase, Mig6 is dynamically regulated during fasting, obesity‐induced diabetes, and ER stress, thus providing a new therapeutic target for unrestrained HGP in T2D.Grant Funding Source: Supported by a Showalter Research Trust Award from IUSM