bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does T Cell Specific Knockdown of Estrogen Receptor‐α Eliminate Premenopausal Protection from Angiotensin II‐Induced Hypertension?
Authors: Uhlorn Josh , Husband Nathaniel A. , Romero‐Aleshire Melissa J. , Pollow Dennis P. , Uhrlaub Jennifer L. , Nikolich‐Zugich Janko , Brooks Heddwen L. 
Published: June 2021

There is extensive evidence that the immune system is required for the development of angiotensin II (Ang II) induced hypertension in males. In contrast, before entering menopause, we have shown that females are protected from T cell‐mediated Ang II hypertension. Following menopause, female protection from T cell‐mediated Ang II hypertension is lost; in the absence of T cells, systolic blood pressure (SBP) responses to Ang II in Rag‐1−/− postmenopausal mice were similar to those seen in premenopausal mice (SBP Δ12 ± 2 mmHg). After adoptive transfer of CD3+ T cells, Ang II significantly increased SBP in postmenopausal females (SBP Δ28 ± 3 mmHg; p<0.05). Thus, we hypothesize that the loss of estrogen in postmenopausal mice eliminates female protection to T cell‐mediated hypertension. Further, we examined if premenopausal protection from T cell‐mediated hypertension was due to T cell‐specific estrogen receptor alpha (ERα) signaling. CD3+ T cells were purified from ERα null mice (ERαKO) and adoptively transferred into cycling, female Rag‐1−/− mice (no T/B cells). Ang II was infused via osmotic mini‐pump for 14 days (490 ng/kg/min). Similar to our previous studies, cycling female Rag‐1−/− mice were resistant to T cell‐mediated Ang II hypertension following T cell transfer from wild type mice (SBP CD3+WT/Ang Δ6 ± 5 mmHg). Additionally, there was no significant difference in SBP when ERαKO T cells were adoptively transferred (SBP CD3+ ERαKO/Ang Δ5 ± 4 mmHg). Flow cytometric analysis of renal CD4+, CD8+, and regulatory Foxp3+ T cells identified that in the absence of ERα, there was an increase in expression of costimulatory receptor CD28 in all three T cell subsets (CD3+ ERαKO/Ang vs. CD3+WT/Ang: CD4+ 138%, CD8+ 144%, Foxp3+ 141%; p<0.05). Our studies suggest that loss of estrogen (menopause) increases female susceptibility to T cell‐mediated hypertension. However, loss of T cell‐specific ERα signaling does not seem to play a key role in premenopausal protection from T cell‐mediated Ang II hypertension.Support or Funding Information1. T32HL0072492. R01HL131834This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Renal Nitric Oxide‐Dependent Mechanisms in Early Sunitinib‐Induced Hypertension
Authors: Witte Jeannine , Mühlbauer Melanie , Braun Diana , Steinbach Antje , Rettig Rainer , Grisk Olaf 
Published: June 2021

Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used in cancer treatment. A major adverse effect of sunitinib is a rapidly developing hypertension associated with reduced renal nitric oxide (NO) availability and increased renal fractional sodium reabsorption (FRNa). We tested if NO‐dependent regulation of renal hemodynamics and FRNa are compromised and if nitrate supplementation has antihypertensive effects in early sunitinib‐induced hypertension.Male Wistar rats were treated with sunitinib at 15 mg/(kg*d). Four days after initiation of sunitinib treatment, renal hemodynamics and renal sodium excretion were investigated. Radiotelemetric experiments were performed to study the effects of nitrate supplementation and soluble guanylate cyclase (sGC) activation on arterial pressure. Nitric oxide synthase (NOS) as well as sGC mRNA and protein abundances were studied in renal tissue.Within four days, sunitinib elicited a 20–25 mmHg arterial pressure rise. NOS inhibition elicited similar reductions in total and renal medullary blood flow in sunitinib‐ and vehicle‐treated rats. NO‐dependent and independent components of endothelium‐dependent renal vasodilation were not compromised in early sunitinib‐induced hypertension. Low dose intrarenal NOS inhibition did not differentially affect FRNa in sunitinib‐ and vehicle‐treated rats. In sunitinib‐treated rats, renal nitrite/nitrate excretion was 60 per cent less than in controls (p < 0.05). However, nitrate supplementation did not reduce arterial pressure and renal sodium balance in sunitinib‐treated rats. While sunitinib treatment had no effects on renal NOS mRNA abundances, it significantly reduced renal cortical sGC α‐ and β‐subunit mRNA abundances as well as renal cortical guanylate cyclase protein expression. Pharmacological sGC activation caused a rapid 15–20 mmHg arterial pressure fall in sunitinib‐treated rats (p < 0.05).We conclude that the NO‐dependent regulation of renal hemodynamics is largely unaltered in early sunitinib‐induced hypertension despite evidence for reduced NO formation. Reduced renal sGC expression and activity may contribute to the early arterial pressure rise in sunitinib‐induced hypertension and cause its nitrate resistance.Support or Funding InformationSupported by the German Research Foundation, Grant‐No. KO 4936/2‐1.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
C1qbp, a Novel Cyclophilin‐D Interacting Protein, Regulates Mitochondrial Permeability Transition and Injury In The Heart
Authors: Baines Christopher P. , Alex Linda , Gutierrez‐Aguilar Manuel , Klutho Paula 
Published: June 2021

The mitochondrial permeability transition (MPT) pore regulates necrotic cell death following diverse cardiac insults. However, so far the only confirmed component of the pore is Cyclophilin D (CypD). Our laboratory has previously identified Complement 1q‐binding protein (C1qbp) as a novel CypD‐interacting molecule and a negative regulator of MPT‐dependent cell death. C1qbp is an acidic homotrimer with proposed roles in inflammation, cancer progression, biogenesis of respiratory chain components, and overall mitochondrial ultrastructure. However, its effects in the cardiac system remain untested. We therefore hypothesized that “activation” of C1qbp would inhibit MPT in cardiac mitochondria and protect cardiac myocytes against necrotic death. We first identified several putative C1qbp ligands using an in silico screen. Treatment of cultured cardiac myocytes with these ligands dose‐dependently protected the cells against oxidative stress‐induced necrosis. To investigate the effects of C1qbp in the myocardium we generated gain‐ and loss‐of‐function mice. Transgenic C1qbp overexpression resulted in decreased mitochondrial respiration and decreased ATP synthase activity, although to our surprise MPT remained unchanged. Interestingly, C1qbp+/− mice also exhibited decreased basal mitochondrial respiration but in this case MPT was sensitized. Neither overexpression nor depletion of C1qbp significantly affected baseline heart function at 3 months of age. When subjected to myocardial infarction, infarct size was unaffected in the C1qbp transgenic mice, consistent with the lack of an effect on MPT. In contrast infarct size was increased in the C1qbp deficient mice, in line with the sensitization of cardiac mitochondria from these mice to MPT Taken together, our results suggest that C1qbp is required for normal regulation of the MPT pore, mitochondrial function, and sensitivity to injury in the heart.Support or Funding InformationNIH HL094404This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Altered Immune Cell Programming in the Kidneys of Obese Dahl Salt‐Sensitive Leptin Receptor Mutant Rats Prior to Puberty
Authors: Shields Corbin Anthony , Poudel Bibek , McPherson Kasi , Garrett Michael , Williams Jan Michael 
Published: June 2021

Recently, we reported that the Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant) strain develops renal injury independent of hyperglycemia and elevations in arterial pressure prior to puberty. However, after puberty, the SSLepRmutant strain develops severe hypertension and chronic kidney disease. In preliminary studies, total RNA was isolated and whole transcriptome paired‐end RNA‐sequencing was performed using an Illumina NextSeq 500 from glomeruli of lean SS wildtype (SSWT) and obese SSLepRmutant rats at 6 weeks of age. The analysis revealed that there were differentially expressed genes in immune cell pathways. Therefore, in the current study, we examined whether there were differences in the expression of various cytokines during the development of renal injury that contribute to immune cell programming in SSWT rats (n=4) and the SSLepRmutant strain (n=4) prior to puberty at 4 and 8 weeks of age via the Bio‐Plex Pro Rat Cytokine 23‐Plex Immunoassay. Protein excretion was significantly higher in the SSLepRmutant strain versus SSWT rats at baseline (65±12 and 2±1 mg/day, respectively) and remained markedly elevated over the course of the study (393±43 and 75±17 mg/day, respectively). The kidneys from the 8‐week old SSLepRmutant rats displayed thickening of glomerular basement membranes, mesangial expansion, and renal fibrosis when compared to their wildtype littermates. We detected marked reductions in immune cell regulation in both SSWT and SSLepRmutant rats between 4 and 8 weeks of age. However, within the SSLepRmutant strain that develops renal injury, we observed significant decreases in T‐lymphocyte (T‐cell) programming cytokines from 4 to 8 weeks of age: IL‐1α (1546±55 to 1060±54 ng/mg), IL‐5 (15±1 to 11±0.3 pg/mg), IL‐6 (30±1 to 24±1 pg/mg), IL‐13 (23±20 to 11±1 pg/mg), TNFα (18±2 to 11±1 pg/mg), and IL‐17 (1227±70 to 151±76 ng/mg) respectively. In conclusion, these data indicate that reductions in cytokines responsible for T‐cell programming in the kidney may play an important role in the development of renal injury associated prepubertal obesity.Support or Funding InformationThis work was supported by P20GM104357 and R01DK109133‐01.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Isolevuglandin Peptide Modification and Proteasomal Processing Contribute to Autoimmune‐Mediated Hypertension
Authors: Patrick David M. , Xiao Liang , Barbaro Natalia R. , Ao Mingfang , Ormseth Michelle J. , Stein C. Michael , Kirabo Annet , Harrison David G. 
Published: June 2021

An estimated one‐third of the world's population suffers from hypertension. Over the last decade, it has become clear that immune activation contributes to hypertension. Reactive oxygen species (ROS) have been shown to be an important activator of this disease. Isolevuglandins (isoLG) are oxidation products of fatty acids that form as a result of ROS. These molecules adduct covalently to lysine residues of proteins. These modified proteins are presented within the major histocompatibility complex type I (MHC‐I) molecule and activate T‐cells, implying a role of the proteasome in peptide processing. We hypothesized that isoLG‐adducted peptides contribute to hypertension in SLE and that presentation of isoLG within antigen presenting cells is dependent on proteasomal processing. We found that isoLG‐adducted peptides are markedly enriched in CD11c positive monocytes of patients with systemic lupus erythematosus (SLE). Moreover, cells that display both the monocyte marker CD11c and the activated dendritic cell marker CD86 were also enriched with isoLG‐adducts in patients with SLE. This implies that isoLGs may be participating in activation of antigen presenting cells in SLE. In addition to these studies, we found that the proteasome contributes to the presentation of isoLG‐adducted peptides on the surface of dendritic cells. We previously showed that treatment of mouse dendritic cells with the oxidant tert‐butyl hydroperoxide confers isoLG‐mediated sensitivity to hypertensive stimulus in recipient mice. Interestingly, co‐treatment of mouse dendritic cells with TBHP and proteasome inhibitor attenuates surface isoLG presentation without modification of intracellular isoLG. Moreover, using a novel method employing fluorescence resonance energy transfer (FRET), we found that isoLG‐adducted peptides and MHC‐I interact at the intermolecular level on mouse dendritic cells, strongly suggesting that these peptides are indeed presented within MHC‐I molecules. Co‐treatment of these cells with TBHP and proteasome inhibitor significantly reduced the intermolecular interaction of isoLG with MHC‐I. These studies provide novel insight into the mechanism of isoLG‐mediated hypertension. Additionally, they suggest a novel role for proteasome inhibitors in the treatment of this condition.Support or Funding InformationThis work was supported by the Clinical Pharmacology T32 PHS Grant Number 2 T32 GM 7569‐42This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel Organometallic Complex Prevents Metabolic Risk Factors in Male Adolescent Rats Consuming a High Fat Diet for 10 Weeks
Authors: Crawford Meli'sa S. , Clark William , Sweazea Karen L. 
Published: June 2021

The prevalence of metabolic syndrome has risen 35% since 2012 and over two‐thirds of Americans meet the criteria of obesity, dyslipidemia, hyperglycemia, insulin resistance and/or endothelial dysfunction. Treating metabolic syndrome is a challenge due to increasing consumption of energy dense foods and lack of compliance with dietary or exercise interventions. The aim of this study was to examine the effects of a novel organometallic complex (OMC) on these metabolic risk factors (obesity, hyperglycemia, dyslipidemia, endothelial dysfunction) in rats fed a high fat diet (HFD) for 10 weeks. Six‐week old male Sprague‐Dawley rats were divided into two dietary groups: standard chow or a HFD composed of 60% kcal from fat. Rats were further divided and treated with OMC in their drinking water at one of the following doses: vehicle (0 mg/mL), 0.6 mg/mL or 3.0 mg/mL. High fat feeding for 10 weeks increased body mass (n=5–6, p<0.05), adiposity (n=5–6, p<0.05), and fasting serum glucose concentrations (n=5, p<0.05) of vehicle‐treated rats. OMC did not prevent weight gain or adiposity in HFD‐fed animals. OMC‐treated HFD rats (3.0 mg/mL) had significantly lower fasting serum glucose concentrations compared to HFD‐vehicle rats (n=6, p<0.05) and OMC (3.0 mg/mL) significantly increased HDL‐c in chow‐fed rats (n=6, p<0.05). To examine endothelial dysfunction, isolated mesenteric resistance arteries (100–130 μm, inner diameter) were cannulated and pressurized to 60 mmHg in a vessel chamber. Arteries were then pre‐constricted to 50% of resting inner diameter with phenylephrine in the superfusate then exposed to increasing concentrations of acetylcholine (ACh, 0.0001–100μM). Low dose OMC promoted vasodilation at lower concentrations of ACh in chow‐fed rats compared to vessels isolated from matched vehicle‐treated animals (n=6, p<0.05). Consistent with prior studies, HFD rats developed impaired vasodilation (n=5, p<0.05), whereas both doses of OMC effectively increased endothelium‐dependent vasodilation (n=6, p<0.05). These findings suggest that OMC, particularly at the higher dose evaluated, effectively ameliorated risk factors associated with metabolic syndrome by attenuating hyperglycemia and improving endothelium‐dependent vasodilation in rats fed a HFD.Support or Funding InformationThis study was funded by a grant from Isagenix International, LLC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Protective Role of AMPK in Sepsis‐Associated AKI
Authors: Li Ying , Hall Elanore , Pham Hai , Singh Prabhleen 
Published: June 2021

Acute kidney injury (AKI) significantly contributes to the morbidity and the mortality in critically ill patients. AKI is also an independent risk factor for developing and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited due to incomplete understanding its pathogenesis. In most eukaryotic cells, AMP‐activated protein kinase (AMPK) functions as a principle sensory protein, which monitors the cellular energy status and mediates metabolic adaptation through increasing ATP level and regulating mitochondrial hemostasis. Sepsis is the most common cause of AKI. Using a mouse s‐AKI model induced by cecal ligation and puncture (CLP), we investigated the role of AMPK in the pathogenesis of sepsis‐associated AKI (s‐AKI) and its underlying mechanisms.The GFR was measured by FITC inulin clearance method. At 24 hours post‐injury, the GFR was significantly reduced in CLP mice (345±19 vs. 155±35 uL/min; p=0.004). Treatments with AICAR (an AMPK activator) 24 hours prior to CLP significantly improved the GFR. Additionally, mitochondrial function was evaluated using Seahorse. A significantly increased maximum respiration rate observed in CLP mice was abolished by Pre‐treatment with AICAR. Moreover, mitochondrial DNA copy number and expression of PGC1α, a master regulator of mitochondrial biogenesis were initially increased at 4h’ post CLP injury; then significantly decreased at 24h’ post‐injury, suggesting mitochondrial volume and mitochondrial biogenesis were increased shortly after the injury but eventually dropped. Pre‐treatment with AICAR prevented these alterations at both 4 and 24 hours post CLP. Finally, an elevation of glycolysis, a less efficient pathway compared to oxidative phosphorylation, was observed in response to CLP. This elevation of glycolysis was prevented in mice pre‐treated with AICAR, suggesting activation of AMPK may prevent CLP‐induced alteration of mitochondrial metabolism. Increased glycolysis was not seen at 4h’ post CLP surgery (Figure 1).Our findings provide novel evidence supporting the critical role of activation of AMPK signaling pathway in preventing development and/or progression of AKI induced by sepsis. Activation of AKI may prevent renal dysfunction in s‐AKI through regulating mitochondrial function, biogenesis, and metabolism. AMPK and its signaling pathway may serve as novel therapeutic targets in s‐AKI.Support or Funding InformationNIH R01DK107852VA Merit Review BX002175NIH R03 DK101841This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Carotid baroreflex responses to simulated hypotension are blunted during passive whole‐body heat stress in young women
Authors: Allen Dustin , Huang Mu , Lenz Kelly , Petric Ursa Bezan , Keller David , Davis Scott L. 
Published: June 2021

Previous studies have proposed that carotid baroreflex (CBR) function is potentially compromised during heat stress, thus possibly disrupting the ability to maintain arterial blood pressure in the heat (e.g., decreased orthostatic tolerance during hyperthermia). Recently, we demonstrated that CBR function is preserved, if not enhanced, during a passive whole‐body heat stress (WBH) in young healthy men. What remains unknown is how CBR function is impacted by hyperthermia in women. Therefore, the purpose of this study was to test the hypothesis that CBR‐mediated responses are preserved during a passive WBH in young women. Changes in mean arterial pressure (MAP) and HR were assessed in 7 healthy women (age: 21±1 yrs, height: 171±5 cm, weight: 66±5 kg, BMI: 23±2 kg/m2) using 5‐s trials of neck pressure (NP, carotid hypotension) and neck suction (NS, carotid hypertension) ranging from +40 to −80 Torr during normothermia (NT) and WBH (increased core temp ~1.0 °C) conditions. To assess the CBR control of MAP and HR, a separate two‐way repeated measures ANOVA was utilized for 1) hypertensive stimuli (i.e., NS: −20, −40, −60 & −80 Torr) and 2) hypotensive‐stimuli (i.e., NP: +20 & +40 Torr). Additionally, the time‐to‐peak responses for HR and MAP, separately, in response +40 Torr & −80 Torr trials were examined between thermal conditions using paired t‐tests. During WBH, the CBR‐mediated increases in MAP and HR in response to NP were blunted (main effect of thermal condition p=0.02 and p=0.02, respectively). While the CBR‐mediated decreases in MAP in response to NS were not different between thermal conditions (main effect of thermal condition p=0.34), decreases in HR were markedly greater during WBH (main effect of thermal condition p<0.001). Additionally, the time‐to‐peak responses for MAP and HR were not altered between thermal conditions for either NP or NS trials (p > 0.05 for all comparisons). Taken together, these data suggest the CBR control of MAP and HR during simulated hypotension is blunted in females during passive WBH, while the control of MAP and HR seems to be preserved, if not enhanced, during simulated hypertension. Contrary to our findings in young men, these results suggest there are sex differences in CBR function during WBH. This diminished ability to increase MAP and HR in response to a hypotensive stimulus during hyperthermia may be a key component in reduced orthostatic tolerance in females during WBH.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Five Nights of Sleep Restriction Attenuates Microvascular Endothelial Function
Authors: Craighead Daniel H. , Nahmod Nicole G. , Buxton Orfeu M. , Chang Anne‐Marie M. , Alexander Lacy M. 
Published: June 2021

Adequate sleep is requisite for optimal physiological function, including microvascular endothelial function. Short‐term sleep restriction (5 hours/night) negatively alters glucose metabolism and may also impair microvascular endothelial function via increased sympathetic nervous system activity and inflammatory pathways. The cutaneous microvasculature represents an accessible, well‐described vascular bed to non‐invasively assess the effects of sleep restriction on microvascular function. Our objective was to evaluate cutaneous microvascular endothelial function during baseline sleep replete conditions (10 hours/night time in bed), after 5 nights of sleep restriction (5 hours/night), and again after 2 nights of recovery sleep repletion. This was part of the Sleep Restriction Study (PI: Chang), an 11‐day inpatient study that took place in the Penn State University Clinical Research Center, during which diet and physical activity were controlled. Eight young, healthy men (23.3 ± 3.4 years) participated in the study. Cutaneous microvascular function was measured utilizing a standardized local skin heating protocol to induce endothelial nitric oxide‐synthase‐dependent vasodilation during all three study phases (baseline, sleep restricted, recovery). Red cell flux (laser Doppler flowmetry) was continuously measured on the ventral forearm at thermoneutral temperature (33 °C) and throughout local heating 0.5°C·5 s−1 to 42 °C until a stable (20 min) plateau had been reached. Red cell flux was normalized to cutaneous vascular conductance (CVC: flux·MAP−1) and expressed as a percentage of maximum CVC (43°C: %CVCmax). Compared to the baseline sleep replete state, the response to local heating was attenuated by 10% after 5 nights of sleep restriction (baseline: 89.2 ± 2.0, restricted: 80.4 ± 3.0 %CVCmax; p=0.045) and fully recovered after 2 nights of recovery sleep (88.7 ± 1.8 %CVCmax; p=0.99 compared to baseline). Maximum CVC was not affected by sleep restriction (all p>0.05). These results suggest that 5 nights of sleep restriction impairs microvascular endothelial function, likely through attenuated nitric oxide‐dependent vasodilation, but that 2 nights of recovery sleep restores microvascular endothelial function in young, healthy men.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.