bluuebunny/crossref_metadata_2025_split huggingface dataset:
JAK/STAT activation induced by Angiotensin II in rats isolated pancreatic islets.
Authors: Alves Eduardo Silva , Haidar André Abou , Quadors Caren DalMoura , Carvalho Diego Soares , Morgan Daniela , Rocha Marlene Santos , Carpinelli Angelo Rafael , Hirata Aparecida Emiko 
Published: June 2021

Angiotensin II (Ang II) controls blood pressure, electrolyte balance, cell growth and vascular remodeling. In addition Ang II activates NAD(P)H oxidase in several tissues and has an important participation in the control of insulin secretion. There is a growing body of evidence demonstrating the occurrence of hypertension, insulin resistance and impairment of pancreatic beta cell function in the development of type II diabetes. In several tissues, Ang II induces JAK/STAT activation and phosphorylation which involve superoxide generation from NAD(P)H oxidase. The aim of the present study was to study the JAK/STAT association stimulated by Ang II. For this purpose, isolated pancreatic islets were incubated in presence or absence of ANG II (10− 8M). Samples were immunoprecitipated with anti‐JAK2 antibody and immublotted with anti‐STAT1 or STAT3 antibodies. Western blotting analysis showed that Ang II induced an increase JAK2/STAT1 (42%) and STAT3 (38%) association when compared with control group (glucose 2.8mM). In addition Ang II was also able to induce a three‐fold increase in protein content of others kinases such as ERK1/2.Financial Support: Fapesp
Reduced reactive oxygen species generation in rostral ventrolateral medulla suppresses the pressor response induced by the excitation of the paraventricular nucleus of the hypothalamus in spontaneously hypertensive rats
Authors: Nishihara Masaaki , Hirooka Yoshitaka , Matsukawa Ryuuichi , Ito Koji , Kishi Takuya , Sunagawa Kenji 
Published: June 2021

BackgroundIncreased generation of reactive oxygen species (ROS) in the rostral ventrolateral medulla (RVLM) contribute to the neural mechanism of hypertension. The RVLM receives excitatory synaptic inputs from the paraventricular nucleus (PVN). It is also suggested that the angiotensin II type 1 receptors in the RVLM are activated by the PVN stimulation. Therefore, we examined whether the excitatory synaptic inputs derived from the PVN mediate the ROS in the RVLM or not.Methods and ResultsWe used 14 to 18‐week‐old male Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). We transfected adenovirus vectors encoding manganese superoxide dismutase gene (AdMnSOD) into the bilateral RVLM. Then, we microinjected bicuculline (BIC) (100pmol) into the unilateral PVN on day 7 after gene transfer. Microinjection of BIC into the PVN increased mean arterial blood pressure (MAP) in both SHR and MnSOD‐transfected SHR, however, the pressor response was significantly attenuated in MnSOD‐transfected SHR (SHR: 33±2 mmHg; MnSOD‐transfected SHR: 20±1 mmHg, n=5, P<0.05). Overexpression of MnSOD in the RVLM did not suppress BIC‐elicited MAP elevation in WKY rats (WKY rats: 14±1 mmHg; MnSOD‐transfected WKY rats: 13±1 mmHg, n=3).ConclusionExcitatory synaptic inputs arising from activation of the PVN to the RVLM are mediated, at least in part, by ROS generation in SHR, but not in WKY.
Short chain fatty acid supplementation increases MUC2 expression and mucin production in a short bowel piglet receiving TPN
Authors: Nehrling Erica , Bartholome Anne , Albin Dave , Tappenden Kelly Anne 
Published: June 2021

Total parenteral nutrition (TPN) is associated with goblet cell atrophy increasing the risk of bacterial translocation. Butyrate has been shown to enhance mucin production and may be an effective clinical treatment for TPN associated intestinal atrophy. This study assessed the effect of butyrate and short chain fatty acid (SCFA) mixtures on MUC2 expression at transcriptional and translational levels in a short bowel syndrome piglet receiving TPN. Piglets underwent massive small bowel resection and received saline, 9mM butyrate, 60mM butyrate or SCFA mixture parenterally for 12 or 72 hours. Quantitative real time PCR showed an increase in MUC2 expression in 9mM compared to other treatments (p=.04). High iron diamine alcian blue stain revealed a trend increase (p=.102) of sulfated mucins in jejunal villi in 9mM over other groups. MUC2 expression tended to increase over time in the ileum regardless of treatment (p=.069). Augmentation of MUC2 and sulfomucins in the proximal bowel by butyrate supplemented TPN enhances barrier function and decreases the risk of bacterial translocation thereby lending support to the use of butyrate as an efficacious treatment of TPN associated intestinal atrophy.Grant Funding Source: NIDDK 5R01DK057682
Adrenergic tone does not tonically restrain limb venous compliance in healthy humans
Authors: Sielatycki John A. , Spilk Samson J. , Monahan Kevin D. 
Published: June 2021

Previously we reported that sympathetic nervous system activation, induced via baroreceptor unloading, acutely decreased calf venous compliance in men. To test the hypothesis that sympathetic nervous system outflow tonically restrains limb venous compliance in healthy humans we studied 7 men (30±4 years old, mean±SE) before and during systemic alpha‐adrenergic (0.1428 mg/kg phentolamine priming dose over 5 min followed by 0.01428 mg/kg/min maintenance dose) and beta‐adrenergic blockade (0.25 mg/kg propranolol priming dose over 15 min followed by 0.004 mg/kg/min maintenance dose). Venous compliance was determined in supine subjects by inflating a thigh venous collecting cuff to 60 mmHg for 8 min, then decreasing pressure at a rate of 1 mmHg/s while measuring calf volume (strain gauge plethysmography). The slope of the pressure‐compliance relation (compliance=β1+2*β2*cuff pressure), which is the first derivative of the quadratic pressure‐volume relation [(Δ limb volume)=β0+β1*(cuff pressure)+β2*(cuff pressure)2] during reductions in collecting cuff pressure, was used to quantify venous compliance. Calf venous compliance was not increased by adrenergic blockade (−2.11±0.43 and −1.49±0.18 before and during adrenergic blockade, respectively). These data suggest that adrenergic tone does not tonically restrain calf venous compliance in healthy men.Support: NIH HL92309, AG24420 and M01 RR10732
Autonomic regulation in patients with diabetic neuropathy
Authors: Wang Siqi , Randall David C , Knapp Charles F , Nelson Kevin R , Patwardhan Abhijit R , Kilfoil Peter J , Evans Joyce M 
Published: June 2021

Cardiac and vascular damage resulting from autonomic neuropathy is a complication of diabetes that often goes undiagnosed. The aims of this study were 1) to quantify damage to cardiac and vascular function in patients diagnosed with peripheral neuropathy, and 2) to develop noninvasive measures to diagnose autonomic neuropathy.METHODSContinuous blood pressure, ECG, blood flow and respiration were monitored in 7 able‐bodied subjects (AB), 9 diabetics without (D0), and 7 diabetics with (D1), neuropathy during supine rest and 70° head up tilt (HUT). Mean values, spectral power and partial coherence analyses were used to discriminate groups.RESULTSIn response to HUT, diabetics increased heart rate to higher levels, but were unable to maintain BP as well as did AB. Low frequency spectral power of SBP and high frequency power of RRI were higher in AB than diabetics during rest and HUT. AB had the highest, and D1 the lowest, slope of baroreflex sequences during rest and HUT.CONCLUSIONSOur results support the concept that diabetes diminishes both sympathetic and parasympathetic influence on cardiac and vascular function and suggest that noninvasive indices may help discriminate patients with autonomic neuropathy. Supported by NIH RO1 NS39774, Kentucky NASA EPSCOR WKU 52611, and UK GCRC USPHS grant #M01RR02602. We acknowledge contributions of A Hartman, RN, L Krompak, L Mohney, D Silcox and R Schneider.
The time course of transcriptional regulation in anoxic fibroblasts: Implications for Carpal Tunnel Syndrome
Authors: Pierce Christine Walker , Tucci Michelle A. , Benghuzzi Hamed 
Published: June 2021

Hypoxia is the initial cellular insult observed in carpal tunnel syndrome. While much is known about the disease progression, little is known about its molecular basis. These studies sought to determine the transcriptional regulation in fibroblasts subjected to anoxia with respect to HIF‐1α and TGF‐β1 expression.MethodsMRHF fibroblasts were cultured under anoxic conditions for up to 72 hours alongside normoxic controls. mRNA levels relative to baseline were determined by real‐time PCR. GAP‐DH was used as the reference standard for normalization and relative quantification of fold‐differences in mRNA expression were determined by the comparative CT method.ResultsTranscriptional up‐regulation of both HIF‐1α and TGF‐β1 were observed in response to anoxia with peak up‐regulation occurring at 15 min of anoxia exposure for both HIF‐1α and TGF‐β1. HIF‐1α showed a 7.3‐fold increase relative to baseline, and this increase was sustained over time. In contrast, TGF‐β1 was increased 3.3‐fold over baseline, but this increase was only transient.ConclusionBoth HIF‐1α and TGF‐β1 have been shown to regulate the expression of connective tissue growth factor (CTGF). The pronounced and sustained up‐regulation of HIF‐1α observed in these studies suggests that CTGF expression in hypoxic carpal tissues is predominantly under the regulatory influence of HIF‐1α.
The Novel Soluble Guanylate Cyclase Activator PPCA Reverses Acute Hypoxia‐induced Pulmonary Hypertension in Dogs
Authors: Wang Tao , McCefferty Gerald P. , Schnackenberg Christine G. , Jucker Beat M , Willette Robert N. , Behm David J. 
Published: June 2021

Nitric oxide (NO) plays a critical role in regulating pulmonary vascular tone. Impaired bioavilability of the NO receptor, soluble guanylate cyclase (sGC), and/or response to endogeneous NO has been implicated in the pathogenesis of pulmonary hypertension (PH). We hypothesize that activating sGC in a NO‐independent manner will provide a valuable therapy for patients with PH.We generated a novel NO‐independent type 2 sGC activator, PPCA, and tested it in a canine model of hypoxia‐induced pulmonary hypertension. Under normoxic conditions PPCA dose‐dependently (3–100 μg/kg, IV) decreased mean arterial pressure (MAP) and pulmonary arterial pressure (PAP) in anesthetized and catheterized beagle dogs (n=5). Following 20 minutes of hypoxia (10% O2), either saline or PPCA (15μg/kg, IV) was administered. PPCA significantly decreased PAP (−25.1±4.1%) vs. vehicle (−7.6±1.4%, P< 0.05), MAP (−16.1± 0.1%) vs. vehicle (−2.7±0.1%, P<0.05), PCWP and LVEDP. In addition, PPCA improved SaO2 and relieved labored breathing as compared to vehicle controls. In contrast, renal blood flow, LV dP/dtmax and cardiac output were not altered by PPCA. Early administration of PPCA (30μg/kg, IV) at 5 minutes after hypoxia completely blocked the hypoxic pulmonary vasoconstriction for over 80 minutes.These data suggest that activation of sGC by PPCA improves pulmonary hemodynamics and function in hypoxia‐induced pulmonary hypertension.
Epigenetic programming of pulmonary vascular dysfunction in mice
Authors: Rexhaj Emrush , Sartori Claudio , Scherrer Urs 
Published: June 2021

Fetal insults predispose to premature cardiovascular disease later in life. In mice, male offspring of restricted diet pregnancy (a model mimicking preeclampsia in humans), display pulmonary vascular dysfunction and transmit this dysfunction to the next generation. The mechanism is unknown. Epigenetic alterations may result in stable changes of gene expression that are transmitted throughout generations.To test for this possibility, we examined the effects of the histone deacetylase inhibitors Butyrate (2 mg/kg/day, i.p for 2 wks) and trichostatin on pulmonary DNA methylation and vascular function in male offspring of restricted diet pregnancies of the 1st and 2nd generation.In offspring of restrictive diet pregnancies pulmonary DNA methylation was significantly impaired (P=0.02 vs. controls). Butyrate normalized pulmonary DNA methylation and pulmonary vascular responsiveness to acetylcholine in vitro (P<0.0001 vs. vehicle) and to hypoxia in vivo in offspring of the 1st generation, and prevented transmission of vascular dysfunction to the next generation (P<0.0001, Butyrate vs. vehicle). Trichostatin had similar effects.We demonstrate for the first time that restrictive diet pregnancy alters pulmonary DNA methylation and pulmonary vascular function by an epigenetic mechanism. We speculate that epigenetic mechanisms may underpin vascular dysfunction in offspring of preeclampsia in humans.
Blood pressure independent sexual dimorphism in proteinuric response to high salt intake in Sprague‐Dawley rats.
Authors: Byrd Charlene Abadie , Rands Vicky F , Prieto Minolfa C , Navar L Gabriel 
Published: June 2021

We examined if changes in blood pressure and proteinuria during chronic salt intake exhibit sex disparities in age‐matched male (♂; N=10) and female (♀; N=10) Sprague‐Dawley (SD) rats subjected to either normal (0.7% NaCl) or high salt (8% NaCl) diets for 2‐weeks. Metabolic studies, systolic blood pressures (SBP) measured by tail‐cuff method and proteinuria in 24‐h urine samples, were performed. Baseline SBP was not different between genders (♂:119.1±3 vs. ♀:119.0±4 mmHg) or after 2‐weeks on HS diet (♂:129.0±5 vs. ♀:125.6±6 mmHg). HS intake induced proteinuria in both sexes; however it was greater in male than in female rats [Day ‐1(♂:5±1 vs. ♀:3±1); Day 9 (♂:36±3 vs. ♀:17±2 mg/day); p<0.01]. By day 13, body weights were higher in ♂ than ♀ rats; however there was no difference with salt load [(male NS: 330±8 versus male HS: 324±7 g); ♀ NS: 217±12 vs. ♀ HS: 226±4 g)]. There were no sex dependent differences in food intake after it factored by body weight (♂ NS: 11±1 g/kg BW; ♂ HS: 12±1 g/kg BW; female NS: 11±2 g/kg BW; female HS: 13±1 g/kg BW; p=no significant). SBP under HS intake did not exhibit sexual dimorphism; however the augmented proteinuria in male rats may reflect a greater predisposition to develop renal injury with high salt consumption than female rats.Grants from the APS (2009 Frontiers in Physiology Research Host Awardees Program); NIH (P20‐RR‐017659; Tulane‐BIRCWH K12HD043451 award).
Novel role of NF‐κB‐dependent miR‐146a induced by diazoxide preconditioning in stem cell survival
Authors: Suzuki Yoko , Kim Ha Won , Haider Husnain Kh , Ashraf Muhammad 
Published: June 2021

We have previously reported that preconditioning (PC) of bone marrow‐derived mesenchymal stem cells (MSCs) with diazoxide (DZ) improved their survival via NF‐κB signaling. MicroRNAs (miRs) are critical regulators for a wide variety of biological events including apoptosis and differentiation. However, the role of DZ‐induced miRs in stem cell survival remains unknown. Here we show that miR‐146a is the major miR induced by DZ treatment and plays a pivotal role in MSCs survival through NF‐κB signaling. PC of MSCs with DZ (200 μM) for 3 hrs significantly increased phosphorylation of Akt as well as nuclear NF‐κB translocation, thereby improving MSCs survival as evaluated by lactate dehydrogenase (LDH) release assay (45% decrease). Importantly, miR‐146a expression was increased by DZ treatment and knockdown of miR‐146a abolished DZ‐induced cytoprotective effects. In addition, knockdown of NF‐κB ablated DZ‐induced miR‐146a expression as well as MSCs survival, indicating miR‐146a is a downstream of NF‐κB and plays a key role in stem cell survival. We are in the process of determining the target genes of miR‐146a by using PCR array as well as computational analysis. Together, these data demonstrated that cytoprotection afforded by PC with DZ was regulated by miR‐146a which may be a novel therapeutic target for stem cell transplantation therapy.Grant supports: NIH R37 HL074272, HL080686, HL087246, HL087288, HL089535
X‐ray, proton and iron ion irradiation all increase adhesiveness of aortic endothelium and may accelerate development of atherosclerosis.
Authors: Kucik Dennis F , Khaled Saman , Gupta Kiran , Wu Xing , Yu Tao , Chang Polly Y 
Published: June 2021

Radiation from a variety of sources is associated with increased risk of atherosclerosis. The molecular mechanism for this is not known. With the hypothesis that radiation's pro‐atherogenic effect is due, at least in part, to a direct, pro‐adhesive effect on vascular endothelium, our objective was to determine the adhesive response of cultured primary human aortic endothelial cells (HAECs) to both X‐rays and the high energy radiation likely to be encountered in prolonged space flight.Vascular EC adhesiveness was assayed using a portable flow‐chamber adhesion assay for X‐rays at UAB and for components of cosmic radiation (iron ions and protons) at Brookhaven National Laboratory. Adhesiveness was scored as the number of un‐irradiated monocytic cells that adhered to HAECs per minute under physiological shear stress. We found that radiation increased HAEC adhesiveness, and that the effect depended on dose, time, and type of radiation. Changes in expression of HAEC adhesion molecules, however, were small and may not account for the pro‐adhesive effect.We conclude that both X‐rays and cosmic radiation increase HAEC adhesiveness, with the potential to increase risk for atherosclerosis. Current work is aimed at identifying molecular mechanisms. Results will be compared to pro‐atherogenic effects of all three types of radiation in a mouse model.This work was supported by a grant from NSBRI through NASA NCC 9–58.
Early and late effects of iron deficiency on heart and baroreflex function
Authors: Chew Herbert G , Almaw Bethelhem H , Gandy Kayla C , Oh Wunyong , Tolhurst Matthew J 
Published: June 2021

Iron deficiency (ID) induces cardiac and neural alterations, such as cardiac hypertrophy and apoptosis, electron transport dysfunction, and brain mitochondrial disruption. Cardiac norepinephrine (NE) depletion suggests chronically high sympathetic nervous system (SNS) traffic to the heart. Thus, ID would be expected to affect heart function and blood pressure, and our previous experiments have shown baroreflex alterations after 4 weeks of ID.HYPOTHESES(1) Chronic high SNS output initially leads to a hyperfunctional heart with higher left ventricular pressure (LVP) and heart rates (HR) at each mean arterial pressure (MAP), and (2) eventual depletion of NE, along with heart apoptosis and debility, is coincident with reduced LVP and HR at all MAP.METHODSRats were fed control (CN) or ID diets for 2 or 4 weeks. Baroreflex experiments were conducted using ramp (before and after atropine) and steady state protocols. Hearts were excised for Langendorff experiments to obtain LVP at set flow rates.RESULTSHematocrit verified ID (p ≤ 0.05); heart mass verified hypertrophy. Baroreflex preliminary data suggests higher HR at all MAP at 2 weeks, but lower HR after 4 weeks; experiments continue at time of writing. Langendorff data indicates higher LVP with ID at 2 weeks, but lower LVP after 4 weeks.CONCLUSIONChanges with ID are adaptive at 2 weeks but pathological after 4 weeks. Supported by WY INBRE (LC4090).
Prolonged treadmill walking attenuates ischemic pressor response and baroreflex control in Yucatan pigs with femoral artery occlusion
Authors: Yang Hsiao Tung , Terjung Ronald L , Bowles Douglas K , Laughlin Harold M 
Published: June 2021

Exercise‐induced hypertension can be extensive in intermittent claudicants (Bakke et al., 2007), likely due to exaggerated sympathetic activation, in part, from peripheral muscle afferents. To study whether exercise training alleviates this ischemic pressor response, Yucatan pigs (35 to 40 kg) received femoral artery occlusion. One wk later, pigs either ran on a treadmill (12 wk, 5 d/wk, at 3.1 mi/hr 0% grade) until fatigue (~30–60 min) (Tr: n=9), or limited to cage activity (Sed: n=8). A stress test by running @1 to 5 mile/h; Aortic blood pressure (BP), heart rate (HR) and collateral blood flow (BF) were monitored at each speed. Baroreflex function was assessed by adenosine (Aden) or Phenylephrine (PE) i.v. BP was 158±2.8 and 140±3.3 at wk 3, and 135±5.8 and 122±4.1 mmHg at 12 wks in Sed and Tr groups (p<0.05), respectively. BFs was ~24% higher in Tr as compared to Sed animals (122±25.3 ml/min; p>0.05). The slope for HR increase to Aden‐induced BP decline was 0.30±0.11 in Tr and 1.6±0.43 in Sed group (p<0.01); whereas, HR decreases to BP increases by PE were not different between groups. Our data showed that exercise training can reduce the exercise‐pressor response, coincident with a modified baroreflex control and possibly related to a modified peripheral muscle afferent input. These findings imply that physical training can temper the exercise‐triggered hypertension in claudicants.Supported by NIH P01HL 52490
Endothelial Control of Coronary Vascular Tone is Altered After MI: Interactions of Nitric Oxide and Prostanoids with Endothelin
Authors: de Beer Vincent J , Taverne Yannick JHJ , Duncker Dirk J , Merkus Daphne 
Published: June 2021

Nitric oxide (NO) and prostanoids induce coronary vasodilation directly, but also indirectly by modulating endothelin (ET)‐mediated vasoconstriction. We have shown that ET‐induced coronary vasoconstriction disappears after myocardial infarction (MI). We aimed to investigate the interactions between NO, prostanoids and ET in control of coronary tone after MI.Changes in coronary tone in response to ETAB blockade with Tezosentan alone and following inhibition of eNOS (LNNA) or cyclooxygenase (Indomethacin) were measured in chronically instrumented swine (27 normal; 14 MI), at rest and during exercise (EX).In normal swine, LNNA and Indo caused coronary vasoconstriction (decrease in cvSO2) at rest and during EX and increased the vasodilator effect of tezosentan, particularly during EX.In swine with MI, the vasoconstrictor effect of LNNA was decreased. A vasodilator effect of tezosentan was uncovered after LNNA, however this effect was decreased as compared to normal swine. Indo‐induced vasoconstriction was maintained after MI, while a vasodilator effect of tezosentan was unmasked at rest and during EX. This effect was increased compared to normal swine.Our results show that both NO and prostanoids exert their vasodilator influence on the coronary vasculature at least in part through suppression of the endogenous ET system, particularly after MI.Supported by Netherlands Heart Foundation (2000T042)
LOSARTAN TREATMENT EFFECT ON NAD(P)H OXIDASE ACTIVATION IN ISOLATED PANCREATIC ISLET OF INSULIN RESISTANT MODEL.
Authors: Haidar André Abou , Alves Eduardo Silva , Quadros Caren Dal'Mora , Carvalho Diego Soares , Morgan Daniela , Rocha Marlene Santos , Carpinelli Angelo Rafael , Hirata Aparecida Emiko 
Published: June 2021

ObjectiveThe aim of this project was to evaluate the RAS inhibition on protein expression and activation of components of NAD(P)H oxidase enzyme in pancreatic islets of experimental model of insulin resistance.Methods and ResultsInsulin resistance was induced by neonatal treatment with monosodium glutamate (MSG). MSG and controls (CTL) received losartan (30mg/Kg/dia) or equal volume of vehicle by gavage for 8 days. The protein expression of p47PHOX subunit was assessed by Western Blot. Pancreatic islets of MSG animals showed an increase of 15% in protein expression of p47PHOX compared with the CTL group. However, treatment with losartan in the MSG group led to 30% of decrease in expression of this protein. Liver of animals MSG, showed a significant increase (p<0.01) of the p47PHOX content compared to CTL which was reversed after losartan reaching to CTL levels. Increased superoxide generation in pancreatic islets of MSG animals was blunted after losartan treatment.ConclusionWe conclude that losartan treatment reduces the expression of subunit p47 PHOX in both hepatic tissue and islets of MSG rats which may act as an important modulator of insulin resistance of this animals.