bluuebunny/crossref_metadata_2025_split huggingface dataset:
The antioxidant role of Prdx6 on acute lung injury
Authors: Wang Yan , Fisher Aron 
Published: June 2021

OBJECTIONEstablished the antioxidant function role of Peroxiredoxin 6 (Prdx6) to acute lung injury in vivo or in vitro.METHODS100% O2 exposure or H2O2 treatment was used to induced acute lung injury models on intact mice or isolated lung type 2 cells; mice/cells survival rates or lung lavage analysis was applied for evaluating the common defending effect of Prdx6; Tunel assays observed cell apoptosis; Diphenylphosphine (DPPP) fluorescence was used to probe the degree of cell membrane lipid peroxidation.RESULTSPrdx6 knockout (KO) mice showed most susceptibility to 100% O2 exposure with shorter survival time and more severe lung injury; on the contrary, Prdx6 overexpression (Tg) mice presented enhanced defending against oxidative lung injury; under varied doses of 50 to 500uM H2O2 treatment for 1 to 24h, Prdx6 KO mice presented dose‐ and time‐related cell injury by increasing the percentage of apoptotic cells, and Tg Prdx6 mice showed least percentage of apoptotic cells; while, the degree of lung type 2 cell membrane lipid peroxidation was probed most serious remarkable in Prdx6 KO mice compared to WT mice and less least in Tg Prdx6 mice under oxidative stress.CONCLUDSIONSPrdx6 plays critical antioxidant function role in defending acute lung injury, which associates with its function of anti‐apoptosis and anti‐lipid peroxidation of cell membrane[HL79063].
Nox2 mediates HGF induced angiogenesis
Authors: Schröder Katrin , Kohnen Andreas , Schütz Susanne , Brandes Ralf P 
Published: June 2021

Hepatocyte growth factor (HGF) promotes angiogenesis and prevents senescence of endothelial cells. Reactive oxygen species (ROS) play an essential role in angiogenesis. One of the most important sources of acutely induced ROS‐production are the members of the NADPH oxidase (Nox) family, in endothelial cells namely Nox2. The angiogenetic potential induced by HGF depends on Nox2. The ability of HGF to induce aortic ring outgrowth was significantly reduced in aortic rigs of Nox2 deficient (Nox2y/‐) mice when compared to wildtype mice. Mobilization of endothelial progenitor cells (EPCs) from the bone marrow into peripheral blood has been suggested to be an essential step in the formation of new vessels. Indeed HGF induced mobilization of EPCs in wildtype mice. This effect of HGF was blocked in Nox2y/‐ mice. Accordingly in wildtype mice HGF induced colony forming unit formation which was absent in Nox2y/‐ mice. In human EPCs HGF acutely induced the production of hydrogen peroxide measured by Amplex Red. After depletion of Nox2‐expression by antisense‐oligonucleotides no HGF inducible ROS production was detectable. Further analyses revealed an HGF inducible phosphorylation of Jak2 and STAT3 which was absent in Nox2 depleted cells.We conclude that EPC mobilization might contribute to the angiogenetic effects of HGF. Nox2 derived ROS play an essential role in HGF inducible EPC‐mobilization and aortic ring outgrowth.
Inhibition of glycogen synthase kinase (GSK)‐3β is involved in isoflurane‐induced delayed cardiac protection
Authors: Kawaraguchi Yoshitaka , Panneerselvam Mathivadhani , Tsutsumi Yasuo M. , Kidd Michael W. , Moreno Ana L. , Patel Piyush M. , Roth David M. , Patel Hemal H. 
Published: June 2021

IntroductionVolatile anesthetics, such as isoflurane, produce acute and delayed cardiac protection. Recently, glycogen synthase kinase (GSK)‐3β has been reported to play an important role in acute protection from ischemia/reperfusion injury via inhibition of mitochondrial permeability transition pore (mPTP) opening. However, involvement of GSK‐3β in delayed protection has not been well understood. Therefore, we examined the role of GSK‐3β in delayed cardiac protection.MethodsMice were exposed to 1.4% isoflurane or 100% oxygen for 30 min under artificial ventilation. After 24 hr recovery, mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion. Infarct size was determined via planimetry. Additionally, after 24 hr recovery, the hearts were excised and lysates of left ventricle were analyzed by immunoblot.ResultsTwenty‐four hours following isoflurane exposure, a reduction in myocardial infarction was observed when compared to control mice (24.0 ± 2.5% vs. 45.1 ± 2.9% of the area at risk; P < 0.05; n = 12, respectively). Western blot analysis showed that phosphorylated GSK‐3β in the isoflurane group significantly increased.ConclusionOur findings suggest that the inhibition of GSK‐3β plays an important role for isoflurane‐induced delayed protection.
β2‐adrenergic receptor gene variation and systemic vasodilation during baroreflex inhibition
Authors: Hesse Christiane , Schroeder Darrel R. , Nicholson Wayne T. , Hart Emma C. , Penheiter Alan R. , Turner Stephen T. , Joyner Michael J. , Eisenach John H. 
Published: June 2021

β2‐adrenergic receptor (ADRB2) gene polymorphisms influence vasodilation, but studies investigating regional or systemic responses conflict, possibly due to counter‐regulatory baroreflex action during systemic β2‐agonist infusion. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (TERB) during baroreflex inhibition. 40 healthy young adults were recruited according to the double homozygous haplotypes: Arg16+Gln27 (n=13), Gly16+Gln27 (n=6), and Gly16+Glu27 (n=21). Arterial pressure was measured by brachial arterial catheter, cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3–7 mg/min), phenylephrine was titrated to restore blood pressure to baseline. TERB was infused i.v. at 33 and 67 ng/kg/min for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR (P = 0.06). For SNP position 16, the highest dose of TERB produced lower SVR in Gly16 vs Arg16 (P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs Arg16 (P = 0.05). During baroreflex inhibition, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16+Glu27 homozygotes, with greater influence from Gly16.Supported from NIH and DFG.
Heat shock protein 70 in the prevention of vascular calcification in renal failure
Authors: Lu Tzong‐Shi , Lim Kenneth , Zehnder Daniel , Yang Yun‐Chun , Yiao Szu‐Yu , Hsiao Li‐Li 
Published: June 2021

Vascular calcification (VC) is highly correlated with cardiovascular mortality in renal failure. Osteo/chondrocytic transformation of human aortic smooth muscle cells (HA‐SMCs) is important in the initiation and progression of VC. In vitro and in vivo studies have shown this process can be driven under hyperphosphatemic and hypercalcemic conditions seen in renal failure. Several transcription factors, including Cbfa1/Runx2 is essential for induction of osteo/chondrocytic transformation.We previously demonstrated that HSP70 prevents vascular permeability changes in certain acute inflammatory processes. Studies have shown significantly higher circulating HSP70 levels in individuals with no evidence of coronary artery disease (CAD), while lower levels in pre‐dialysis patients, and even lower levels in hemodialysis (HD) patients were found.Our results have shown for the first time that heat‐shock treatment induced expression of HSP70 and markedly reduced the extent of calcification in HA‐SMCs, in vitro. Cbfa1 was upregulated in calcified HA‐SMCs, while heat‐shock treatment down‐regulates its expression. Furthermore, HSP70 expression was found to be lower in arteries from renal failure patients compared to healthy controls, ex vivo. In conclusion, HSP70 reduces the development of calcification through the inhibition of smooth muscle cell transformation.
Role of central angiotensinergic mechanisms on the facilitation of the recovery of hemorrhage‐induced hypotension by noradrenergic A2‐lesions
Authors: Freiria‐Oliveira Andre Henrique , Blanch Graziela T. , De Paula Patricia M. , Colombari Eduardo , Menani Jose V. , Colombari Debora S. A. 
Published: June 2021

Lesions of A2 neurons in the commissural nucleus tractus solitarii (cNTS) facilitate the recovery of hemorrhage‐induced hypotension. In the present study we investigated the effects of intracerebroventricular (icv) injections of losartan (AT1 receptor antagonist) on the recovery of arterial pressure (AP) after hemorrhage (4 blood withdrawals, 2 ml/rat, every 10 min) in conscious A2‐lesioned rats. Thirty days before tests, male Holtzman rats (280–320 g) received an injection into the cNTS of anti‐dopamine‐beta‐hydroxilase‐saporin (A2 lesion; 12.6 ng/60 nl, n=6–8) or IgG‐saporin (sham; 12.6 ng/60 nl, n=5–7). Seven and 1 day before tests rats also received an icv cannula and femoral artery and vein catheters, respectively. After the 4th blood withdrawal, hypotension was similar in both A2‐lesioned and sham rats (−62±7 and −73±7 mmHg, respectively). The A2‐lesioned rats treated with saline icv rapidly recovered from hypotension (−7±2 mmHg 20 min later), while sham rats did not completely recover from hypotension (−20±3 mmHg at 60 min). Losartan (100 μg/1 μl) icv did not affect AP in sham rats, however it abolished the recovery of AP in A2‐lesioned rats in the first 30 min of test (−24 ± 6 mmHg). The results suggest that the facilitatory effects of A2 lesions of the cNTS on the recovery of AP after hemorrhage depend, at least partially, on the activation of central angiotensinergic mechanisms.Funded by CNPq, FAPESP.
Role of L‐Citrulline/L‐Arginine Cycle in Hyperoxia‐Induced Decrease of Airway Smooth Muscle Relaxation
Authors: Sopi Ramadan , Gjorgoski Icko , Mladenov Mitko , Lajçi Azem , Jakupaj Muharrem 
Published: June 2021

It was shown that inhibitory nonadrenergic noncholinergic (iNANC) nerve–induced nitric oxide (NO) production and airway smooth muscle (ASM) relaxation are impared after exposure to hyperoxia due to decrease of L‐arginine bioavailability to NO synthase (NOS). Therefore, we tested the hypothesis that L‐citrulline/L‐arginine cycle is active in rat pup airways and supplementation of tissues with L‐citrulline, restores impaired relaxation of ASM after exposure to hyperoxia. Tracheal rings were excised from rat pups 12 days old, exposed to hyperoxia or room air for seven days. In precontracted tracheal smooth muscle (TSM), electrical field stimulation (EFS) was applied to induce relaxation. In hyperoxic group, relaxation was reduced as compare to control group. Incubation of tissues with NOS inhibitor (L‐NAME), reduced relaxant responses in control group. In vitro supplementation of tissues with L‐citrulline reversed EFS‐induced relaxation of TSM of hyperoxic group at control level, but did not have any effect in control group under basal condition. Inhibition of enzymes involved in L‐citrulline recycling, prevented this effect of L‐citrulline.The data demonstrate that L‐citrulline/L‐arginine cycle is active in rat pup TSM and is effective under conditions of reduced bioavailability of L‐arginine to NOS. Presence of L‐citrulline restores hyperoxia‐induced decrease of ASM relaxation.
Lung endothelial dysfunction in heart failure: Role of impaired Ca2+ signaling and cytoskeletal reorganization
Authors: Yin Jun , Kerem Alexander , Kaestle Stephanie M. , Hoffmann Julia , Kuebler Wolfgang M. 
Published: June 2021

Congestive heart failure (CHF) causes lung endothelial (EC) dysfunction, which in turn aggravates lung vascular remodeling and right ventricular failure. Here, we elucidated the mechanisms underlying lung EC dysfunction in a rat model of CHF induced by supracoronary aortic banding. Lung EC dysfunction was evident in CHF as impaired EC‐dependent vasodilation and NO synthesis in response to mechanical stress, acetylcholine or histamine, although expression of endothelial NO synthase was unmitigated. Reconstitution of cytosolic Ca2+ ([Ca2+]i) signaling by Ca2+ ionophore restored NO production. Impaired lung EC [Ca2+]i homeostasis and signaling in CHF in response to mechanical stress, histamine, acetylcholine or thapsigargin was confirmed by real‐time fluorescence imaging, yet was not attributable to downregulation of EC Ca2+ influx channels. Rather, we identified a massive remodeling of the endothelial cytoskeleton by increased β‐actin expression and F‐actin formation, which contributed critically to endothelial dysfunction in CHF, since cytoskeletal disruption by cytochalasin reconstituted endothelial [Ca2+]i signaling and NO production. Our findings show that lung EC dysfunction in CHF results from impaired EC [Ca2+]i signaling, and identify the endothelial cytoskeleton as critical regulator of EC [Ca2+]i homeostasis.Sponsored by EU IP Pulmotension and Kaiserin‐Friedrich Foundation Berlin.
Systemic inflammation suppresses hypoxic and hypercapnic ventilatory responses in rats.
Authors: Windelborn James A , Mitchell Gordon S 
Published: June 2021

Chemoreflex responses to hypoxia and hypercapnia are critical elements of ventilatory control. However, chemoreflexes may be undermined by factors frequently associated with lung disease, such as systemic inflammation. Here, we tested the hypothesis that systemic inflammation suppresses ventilatory responses to hypoxia and hypercapnia in rats. Ventilatory responses were assessed in unanesthetized adult rats via whole‐body plethysmography 1 day after lipopolysaccharide administration (LPS: 1 mg in saline, i.p.). In Lewis rats, LPS suppressed both hypoxic (10.5% O2; vehicle: 90±19%; LPS: 37±11%; p < 0.05) and hypercapnic ventilatory responses (7% CO2; vehicle: 223±22%; LPS: 66±26%; p < 0.05). Splenic iNOS mRNA increased 6.5‐fold (qPCR) in LPS‐treated Lewis rats, demonstrating systemic inflammation. In contrast, there was no evidence for suppressed hypoxic (vehicle: 127±14%; LPS: 92±21%) or hypercapnic ventilatory responses (vehicle: 216±19%; LPS: 239±27%) in LPS‐treated Sprague Dawley rats, nor were splenic iNOS mRNA levels increased. Thus, although LPS sensitivity varies among rat strains, systemic inflammation suppressed chemoreflex responses to hypoxia and hypercapnia. Suppressed chemoreflex responses may impair the ability to respond appropriately to ventilatory challenges in disease states associated with inflammation, including many lung diseases (NIH HL69064 and HL007654).Grant Funding Source: NIH HL69064 and HL007654
Alpha Adrenergic Sensitivity and Temperature in Human Arteries: The Role of Nitric Oxide
Authors: Ives Stephen James , Zhao Jia , Noyes R. Dirk , Andtbacka Robert , McDaniel John , Symons J. David , Hayman Melissa , Wray D. Walter , Richardson Russell 
Published: June 2021

Previously, we have found that increased local temperature exerts a sympatholytic effect in vitro. We hypothesized that this may be due to upregulation in the activity of endothelial nitric oxide synthase (eNOS), reducing the impact of the α‐1 adrenergic receptor agonist phenylephrine (PE).METHODSHuman arteries (350–700uM) supplying skeletal muscle were obtained during pre‐scheduled surgeries. Vessels were dissected into 2mm rings and mounted on a wire myograph. All vessels underwent a stepwise length tension procedure to determine LMAX (≤10% increase in mg developed tension (mgΔ) to 100mM Potassium Chloride; KCL). Vessel function was characterized using KCL, Sodium Nitroprusside, PE, & Acetylcholine dose response curves (DRCs) to determine non‐receptor and receptor mediated vasoconstriction and vasorelaxation. PE DRCs were performed both at 37 and 39°C, which were repeated in the presence of the NOS inhibitor L‐NG‐monomethyl‐arginine (L‐NMMA). Data are mean ± SE.RESULTSPEMAX at 39°C was lower than 37°C (85±32 vs. 241±173 mgΔ). Nitric oxide blockade enhanced vasoconstriction at 37° and 39°C (537±226 and 256±81 mgΔ, respectively).CONCLUSIONThese findings reveal that NO blockade can restore the attenuated PE‐induced vasoconstriction at 39°C to that of 37°C, but also highlight the important role that vasodilators play in the vascular response to vasoconstrictors.Support: NIH grant PO1 HL‐091830
Contribution of nitric oxide to the blood pressure and arterial responses to incremental maximal exercise in humans
Authors: Fisher James P , Campbell Ross , Sharman James E , McDonnell Barry J , Frenneaux Michael P 
Published: June 2021

We sought to determine the contribution of nitric oxide (NO) to the blood pressure (BP) responses to exercise and post‐exercise alterations in arterial stiffness. In 10 healthy subjects (31±5 years), BP, heart rate (HR) and oxygen consumption were measured before, during and after an incremental cycling exercise test. Trials were performed with placebo (saline) or following acute inhibition of NO synthase with NG‐monomethyl‐L‐arginine (L‐NMMA) on separate days, in a randomized, double blind, cross‐over design. Central (aortic) and peripheral (femoral) arterial stiffness was assessed with pulse wave velocity (PWV). BP was increased with L‐NMMA at rest and during sub‐maximal exercise, but not at maximal exercise (mean BP 118±8 vs. 117±5 mmHg, saline vs. L‐NMMA, P>0.05). L‐NMMA had no influence on exercising HR or maximal oxygen consumption (P=ns). Post‐exercise reductions in femoral PWV were attenuated with L‐NMMA (P<0.05), while aortic PWV was increased similarly with either saline or L‐NMMA (P=ns). Our findings suggest that reductions in NO bioavailability cause augmented BP responses to sub‐maximal exercise, but do not lead to exaggerated BP responses to maximal exercise or reduce maximal oxygen consumption. Furthermore, NO is an important contributor to reductions in femoral artery stiffness following maximal exercise in healthy individuals.This research was supported by the BHF.
Cardiovascular responses during acute inspiratory muscle exercise in hypertensive or chagasic cardiomiopathy
Authors: Borile Suellen , Ferreira‐Filho Julio César Aires , Sousa Silvia Beatriz Cavasin , Mello Priscila , Irigoyen Maria Claudia , Krieger Eduardo Moacyr , Consolim‐Colombo Fernanda Marciano 
Published: June 2021

AimTo analyze systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), total peripheral resistance (TPR), cardiac output (CO) and derivative of ventricular pressure (dp/dt) during inspiratory exercise.MethodsCardiovascular parameters were continuously recorded by an indirect blood pressure register device (Finometer) at baseline and during exercise (10 min) with a Threshold® device in 27 hypertensive cardiomiopathy (HCM) and 9 chagasic cardiomiopathy (CCM) patients (LVEF < 45% and inspiratory muscle weakness).Results26% of HCM patients did not finish exercise protocol due to exacerbated increase in blood pressure (ΔSBP > 20mmHg). On the other hand, all patients of CCM group completed the exercise protocol; nevertheless, they showed intense fatigue. There were significant differences when comparing baseline vs. exercise for HCM and CCM groups, respectively, in: SBP (Δ= 9±2 and Δ= 7.6±3 mmHg), DBP (Δ= 4.8±1 and Δ= 4.2±1 mmHg) and HR (Δ= 5.5±1,2 and Δ= 6.6±3 bpm). Only HCM group presented increase in CO (Δ= 0.36 ±0.1 l/min) and dp/dt (Δ= 118±35 mmHg/s). There was no significant difference between HCM and CCM.ConclusionAcute inspiratory muscle exercise caused important hemodynamic alterations, mainly in hypertensive patients. Therefore, before indication of unsupervised inspiratory training, it is necessary to perform one cardiac monitorized session to recommend this type of exercise.
Whole body to gene: Adaptations with high volume bicycle training
Authors: Slivka Dustin Russel , Dumke Charles L , Hailes Walter S , Cuddy John S , Ruby Brent C 
Published: June 2021

Metabolic changes occur with exercise and exercise training. However, whole body change is rarely investigated along with enzymatic and mRNA changes. The purpose of this study was to inclusively describe exercise metabolic adaptation. Ten trained males cycled ~100 miles per day for 21 days. Gas was collected on days 0, 10, and 20 during a graded exercise. Muscle biopsies were obtained before and after exercise on days 1, 11, and 21. Fat oxidation increased (p<0.05), carbohydrate oxidation decreased (p<0.05), and gross efficiency increased (p<0.05) by day 10 without further increases by day 20. CS enzyme activity increased from day 11 to day 21 (p<0.05). B‐HAD and COX enzyme activity did not change. CS mRNA did not change acute exercise or training. B‐HAD mRNA was higher post exercise on days 11 (p=0.041) and 21 than (p=0.048) on day 1. COX mRNA increased with exercise (p=0.001) but did not change over the 21 days. PGC‐1 increased as a result of exercise (p=0.000), but did not increase to the same degree on day 11 and 21 as it did on day 1. UCP3 mRNA decreased by day 21 and showed a trend to increase (p=0.073) as a result of exercise. These data indicate that the rapid training adaptations observed in substrate use and gross efficiency cannot be explained by classical metabolic enzymes in these trained individuals.Supported by Air Force Research Laboratories, FA8650‐06‐1‐679 and the University of Montana Grant Program.
Integrated autonomic control of bronchial blood flow and third generation airway dimensions during exercise
Authors: White Saxon William , McLeod Damian , Quail Anthony , Cottee David , Pitsillides Koullis , Seah Peng , Parsons Gibbe , McIlveen Stephen , Gunther Robert 
Published: June 2021

Neural mechanisms controlling 3rd generation airway blood flow and dimensions were studied in 8 sheep trained to run on a treadmill during moderate exercise O2 uptake 20 ml.kg−1.min−1 for 2 min, 10 min recovery. We measured rapid changes in bronchial blood flow and conductance (Qbr, Cbr), circumference (Circbr) and wall thickness (Thbr), using pulsed‐Doppler flowmetry, transit‐time sonomicrometry, and single crystal sonomicrometry, respectively. At exercise onset Pa rose to 111% (P< 0.05) of resting and HR from 85 b/min to 164 b/min (P< 0.001) before returning in recovery at 5 min. Qbr fell immediately to 91% and to 90% at 1.5 min (P< 0.05), and early in recovery to 84% (P< 0.05) before returning to pre‐exercise levels. Cbr followed a similar pattern (P< 0.05). Circbr fell immediately to 96% (P< 0.001) where it remained for the duration of exercise, and Thbr increased and was sustained during exercise before returning to control levels in recovery. Cholinoceptor block by i.v. methscopolamine bromide modified these responses. Pa rose to 109% of resting (P< 0.01), and HR rose from 120 b/min to 168 b/min (P< 0.001). A minor Qbr and Cbr fall was not significant, and only an immediate transient fall in Circbr was evident (P< 0.01). Thus raised vagal activity dominates the exercise‐induced bronchovascular and airway wall constriction in 3rd generation airways during and after exercise.Funding: Hunter Medical Research Institute