bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Regulation of Blood Pressure in Transgenic Mice Containing ‐217A/G Polymorphism of Human Angiotensinogen Gene in Response to Immobilization Stress
Authors: Jain Sudhir , Pandey Varunkumar G. , Maharjan Srikrishna , Mopidevi Brahmaraju , Arudra Sri Krishna Chaitanya , Kumar Ashok 
Published: June 2021

Stress is a risk factor for hypertension. However, the mechanism by which stress leads to hypertension is unclear. Stress induces glucocorticoid secretion. Increased glucocorticoids trigger DNA binding activity of C/EBPβ and C/EBPδ via glucocorticoid receptors (GR). Here we show that expression of C/EBPβ, C/EBPδ and AGT genes are significantly increased in adrenal medulla, liver and kidney of rats subjected to Immobilization stress (IS).Renin‐angiotensin system (RAS) plays an important role in regulating blood pressure. Transcription factors C/EBPβ and C/EBPδ are important in regulation of human angiotensinogen (hAGT) gene. We have shown that hAGT gene contains an A/G polymorphism at ‐217, and frequency of ‐217A allele is increased in African‐American hypertensive subjects. Nucleotide sequence of hAGT gene promoter containing ‐217A has homology with the consensus CCAAT/enhancer binding protein (C/EBP) and GR binding site. Therefore, we have generated transgenic mice containing either ‐217A or ‐217G haplotype of the hAGT gene. These transgenic mice were subjected to IS. We found that mice containing haplotype ‐217A subjected to IS has 1.72 fold increased expression of hAGT in liver and 8mmHg increase in blood pressure. Whereas the mice containing haplotype ‐217G shows only 1.2 fold increase in hAGT expression and no significant change in blood pressure. These results suggest that stress leads to the differential regulation of human AGT gene.
Sodium reabsorption in the distal convoluted tubule is enhanced in the 11β‐hydroxysteroid dehydrogenase type 2 knockout mouse
Authors: Hunter Robert William , Mullins Linda , Bailey Matthew A , Mullins John J 
Published: June 2021

Mice lacking 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2) exhibit hypertension and renal sodium retention that has been attributed to increased activation of the epithelial sodium channel (ENaC) in the connecting tubule and collecting duct. We tested the hypothesis that increased activation of the sodium chloride co‐transporter (NCC) in the distal convoluted tubule (DCT) also contributes to this phenotype.We compared male 11β‐HSD2 knockout mice at 55 – 65 days of age to wild‐type controls in experiments designed to assess NCC expression and function.Knockout mice exhibited hyperplasia in the DCT (indentified using an anti‐NCC antibody in immunohistochemistry on formalin‐fixed tissue). NCC protein expression was upregulated in knockout mice (immunoblot of whole kidney homogenates; n = 8, p < 0.01) as was expression of the gene encoding NCC, Slc12a3 (Q‐PCR using whole kidney homogenates; n = 8; p < 0.01). The functional consequences of this were assessed by measuring the effect of an acute hydrochlorothiazide bolus on the fractional excretion of sodium in anaesthetised mice.Our results suggest that enhanced sodium chloride reabsorption in the DCT contributes to the hypertensive phenotype in this mouse model of apparent mineralocorticoid excess and provide an insight into the role played by adrenal steroids in the regulation of sodium transport in the distal nephron.
H,K‐ATPase type 2 is required for renal adaptation to pregnancy
Authors: Crambert Gilles , Doucet Alain , Salhi Amel 
Published: June 2021

Renal reabsorption of K+ during dietary K+ restriction requires the stimulation of H,K‐ATPase type 2 by adrenal progesterone (Elabida et al. 2011, Kidney Int. 80, 256–262). Since renal K+ retention has been observed during pregnancy we investigated whether this pathway could be functional in this physiological state.During the late part of gestation in mice, the decrease in renal K+ excretion is accompanied by stimulation of HKA2 mRNA and activity. In this condition, kidney function is disconnected from the dietary conditions since gravid mice increase their food consumption (and their K+ intake) by 15%. HKA2‐null mice are unable to efficiently retain K+ during gestation compared to wild‐type littermate (WT) but maintain normal plasma K+ values (around 3.9 mM). This occurs in parallel with a decrease of the fertility rate (86% vs. 25% of successful gestation in WT and HKA2‐null mice, respectively) and a higher mortality rate during gestation in HKA2‐null mice compared to WT. Both phenotypes are reversed when gravid HKA2‐null are given a K+ supplementation in their drinking water. All together, our results provide evidence that pregnancy is a physiological state where kidney is switched from a K+ secretive to a K+ reabsorptive state because of stimulation of H,K‐ATPase type 2. Moreover, inability to do so, have an impact on the development of the gestation.
High fat feeding modulates apoptotic/autophagic pathways in post ischemic myocardium and confers cardioprotection
Authors: Haar Lauren , Ren Xiaoping , Bertaux-Skeirik Nina , Tranter Michael , Rubinstein Jack , Jones WK 
Published: June 2021

It is known that chronic consumption of a high fat diet leads to pathology including atherosclerosis, obesity, myocardial infarction, and type II diabetes. However, as suggested by clinical data, we have shown in mice that short‐term exposure to high fat feeding induces cardioprotection against ischemia/reperfusion injury.We investigated the mechanism for this high fat diet mediated cardioprotection and hypothesize that high fat mediated cardioprotection influences anti‐apoptotic and pro‐autophagic pathways. Our results show that this cardioprotection is NF‐kB dependent and leads to expression level changes in NF‐κB‐dependent genes that contribute to autophagy and apoptosis. Protein levels of Beclin‐1, a key initiator of autophagosome formation, is significantly increased in the ischemic in the post‐ischemic hearts of mice fed a high fat diet relative to control fed mice. In addition, a decrease in TUNEL stained nuclei in sections post‐ischemic of hearts from high fat fed mice relative to control fed suggest a significant decrease in the number of apoptotic nuclei in the ischemic zone of high fat fed mice. The timecourse of high‐fat diet induced autophagy and decreased apoptosis in ischemic hearts correlates with the timecourse of cardioprotection observed as a result of high‐fat feeding. Ongoing work is focused on comparing the autophagic/apoptotic pathway dependence to further discern the mechanistic basis of the protection. Functional studies will be conducted to assess the therapeutic relevance of this effect.This work was supported by NIH RO1HL091478 (WKJ), NIH T32HL007382 (LH) and Rhen Family Grant (JR)
Inhibition of Protein Kinase β2 Attenuates NOS Uncoupling and Myocardial Dysfunction in Streptozotocin‐Induced Diabetic Rats
Authors: Lei Shaoqing , Li Haobo , Wang Tingting , Liu Yanan , Mao Xiaowen , Hei Ziqing , Irwin Michael G , Xia Zhengyuan 
Published: June 2021

Hyperglycemia induced protein kinase C (PKC) β activation is implicated in diabetic cardiomyopathy, which is also associated with impaired function of endothelial nitric oxide (NO) synthase (eNOS). We postulated that PKCβ2 inhibition may attenuate myocardial dysfunction by rescuing eNOS function and reducing eNOS uncoupling in streptozotocin (STZ)‐induced diabetes. Control (C) or STZ‐induced diabetic (D) rats were treated or untreated with PKCβ inhibitor LY333531 (LY, 1 mg/kg/day) for four weeks. The ratio of peak velocity of early and late diastolic filling (E/A) measured by echocardiography was decreased, while left ventricular isovolumic relaxation time (IVRT) and the heart to body weight ratio were increased in D rats. All of these changes were attenuated by LY (P<0.05 D vs. C). Cardiac O2− and nitrotyrosine production were increased, whereas NO were decreased in D rats. Diabetes induced increase of O2− levels was blocked by the NOS inhibitor L‐NAME, indicating “NOS uncoupling”. In addition, cardiac iNOS expression was increased, while levels of eNOS, p‐eNOS (Ser 1177) and p‐Akt (Ser 473) expression were decreased in D rats. All the alterations were attenuated or reversed by LY. We conclude that PKCβ2 inhibition may attenuate myocardrial dysfunction in diabetes by restoring Akt‐dependent eNOS/NO signaling and maintaining eNOS coupling.Supported by RGC/GRF (782910, 766709)
Viscous dietary fibers added to a high fat diet decrease adiposity, improve glucose control and alter fuel utilization in obese rats
Authors: Brockman David A. , Chen Xiaoli , Gallaher Daniel D. 
Published: June 2021

Viscous dietary fibers reduce the postprandial rise in blood glucose and decrease adiposity in normal and diabetic rats. The purpose of this study was to examine the effects of viscous fibers on fat mass and fuel utilization in a model of diet‐induced obesity. Wistar rats were fed a high fat diet (60% energy from fat) containing 5% fiber as either cellulose (non‐viscous) or one of two highly viscous fibers ‐ hydroxypropyl methylcellulose (HPMC) or guar gum. After 10 weeks of feeding, the HPMC and guar groups had lower fat pad weights and total body fat mass compared to the cellulose group. The guar group had a decreased glucose tolerance test area under the curve (AUC) indicating improved glucose control. AUC during a meal tolerance test was not different with viscous fiber treatment. However, after 3 weeks of feeding, the respiratory quotient (RQ) AUC over 24 hours was increased with HPMC and guar compared to cellulose, implying greater carbohydrate oxidation. The RQ AUC during fasting did not differ between the HPMC and cellulose groups but after a meal it was greater in the HPMC and guar groups. This suggests a quicker transition from fatty acid to carbohydrate oxidation, possibly through decreased insulin resistance. These results indicate that consumption of viscous fibers with a high fat diet can improve glucose control, lower adiposity and increase fuel flexibility.Grant Funding Source: MN Agricultural Experiment Station, MN Obesity Consortium
Discovery of Early Life Plasma Protein Signatures for Asthma Development
Authors: Xu Haili , Radabaugh Timothy , Lu Zhenqiang , Billheimer Dean , Vercelli Donata , Halonen Marilyn , Lau Serrine S 
Published: June 2021

ObjectiveThe objective of our study was to identify plasma proteomic signatures that accompany asthma risk in early life using an antibody array approach.MethodsBlood plasma samples from 2 groups of three‐year‐old subjects enrolled in the Tucson Infant Immune Study were assayed for relative expression of 507 proteins by RayBio's Biotin Label‐based Human Antibody Arrays. The 2 groups were subjects with no asthma by age 9 or wheeze at age 9 (no asthma/wheeze; n=6) and subjects with asthma by age 9 and wheeze at age 9 (asthma/wheeze; n=11). The intensity values of signals from each plate were ranked. Rank differences between the 2 groups were evaluated for each protein using the t‐test. Proteins showing significant group differences were identified by a false discovery rate (FDR) p value of<0.1.ResultsTwo proteins were found to be substantially altered in rank among subjects with asthma/wheeze versus subjects with no asthma/wheeze. The rank of eotaxin‐3 was increased (pFDR = 0.0598) and the rank of erythropoietin was decreased (pFDR =0.0282) in subjects with asthma/wheeze.ConclusionOur study suggests that the relative expression of proteins eotaxin‐3 and erythropoietin in plasma can serve as candidate biomarkers differentiating subjects with from those without asthma/wheeze.Funded by ABCD Pilot Project, P30ES006694 and ES018328
The endothelial cells of ductus arteriosus have a unique gene profile to control vascular morphology
Authors: Liu Norika , Yokota Tomohiro , Maekawa Shun , Yokoyama Utako , Kato Takashi , Minamisawa Susumu 
Published: June 2021

Patency of ductus arteriosus (PDA) is morbid; especially it is a severe problem in preterm infants. Hence, to investigate the mechanism of DA closure is important for pediatrics. The present study focused on endothelial cells (ECs) in the DA because ECs lining vessels have a variety of functions and play a central role in homeostasis of the circulatory system. We hypothesized that ECs of the DA had unique characteristics from other vessels and that they should be the primary target to investigate the molecular mechanisms of the DA‐specific vasoconstriction and vascular remodeling.Using fluorescence activated cell sorter, we isolated pure ECs from pooled tissues from the DA or the aorta of Wistar rat fetuses on the 21st day of gestation (e21) or 30 minutes after birth (day0). The gene profiling of those sorted cells were then analyzed by DNA microarray (GeneChip Rat Gene 1.0 ST Array, Affymetrix). We found 61 genes in e21 and 63 genes in day0 were specifically expressed in DA ECs than in aortic ECs (the data were cut off by p value<0.01 or fold change > 2.0). Among them, the genes related to cell adhesion and blood vessel morphogenesis development, such as Vegf‐a, Tgf‐beta, Tbx1, Fgf10 and Pitx2 were abundant in DA ECs, which indicates those genes play an important role in specification of DA morphology and function.
Measurement of the Binding Strength of Endothelial Progenitor Cells to Vascular Endothelial Cells in Shear
Authors: Prisco Anthony , Greene Andrew 
Published: June 2021

Endotheial Progenitor Cells (EPCs) from the bone marrow participate in angiogenesis. When isolated, cultured and injected intravenously into an angiogenesis incompetent strain, EPCs are capable of restoring angiogenesis. One of the key factors in this restoration is the binding dynamics of the EPC‐endothelial cell (EC) interaction. When treated with TNF‐[alpha], endothelial cells are “activated,” through the upregulation of integrins on the cell surface which contribute to the EPC‐EC interaction. We built a custom in‐vitro flow chamber that exerts a shear stress gradient on cultured cells to determine the extent that EPCs derived from 8 week Sprague Dawley (SD) rats were bound to ECs (3 hour binding period) derived from 1 day SD neonates (Cell Biologics) with and without EC treatment (TNF‐[alpha] (1ng/mL) for 12 hours). We then used the chamber to measure the strength of the interaction. To investigate the mechanism of EPC‐EC binding, we compared the surface protein expression of the ECs treated with TNF‐[alpha], to vehicle treated cells. Using a targeted plasma membrane proteome capture followed by tandem mass spectrometry analysis, differentially expressed membrane proteins revealed several candidates for the EPC‐EC interaction.Supported by NIH082798
Early myocardial contractility depression in female endotoxemic rats
Authors: Goncalves Ronald Paiva Moreno , da Silva Santos J. Eduardo , Guarido Karla Lorena , Assreuy Jamil 
Published: June 2021

Although several in vitro studies have addressed heart function in sepsis, this subject has been scarcely investigated in vivo. Using a pressure‐volume (PV) conductance catheter, we evaluated the cardiac function in situ in Wistar rats injected 6 or 24 h before with E. coli lipopolysaccharide (LPS, 10 mg/kg, i.p.). The rats were anesthetized with xylazine (2 mg/kg) and isoflurane (1–3%), plus lidocaine on surgical sites. The catheter was inserted into the left ventricle (LV) through the carotid artery. Compared to control, stroke work (SW) and LV relaxation time constant Tau were reduced by 57% and 63% in LPS 6 h, and by 36% and 57% in LPS 24 h group, respectively. LV mean pressure was decreased ~ 20 mmHg both 6 and 24 h after LPS (control: 48.9 ± 7 mmHg; p < 0.05). Interestingly, the mean arterial pressure was reduced from 88.7 ± 7.3 in control to 63.2 ± 3.2 mmHg in LPS 24 h, but it was unchanged in LPS 6 h. Heart rate did not change in LPS 24 h, but was increased from 253 ± 21 to 314 ± 13 bpm in control and LPS 6 h groups, respectively. Our study suggests that heart function is impaired in early stages of sepsis, even before the well‐described hypotension, and that this dysfunction may be hidden by compensatory mechanisms.Research support: CNPq and FAPESC (1366/2010‐8).
Hemoperitonium Increases Carbon Monoxide and Reduces Platelet Aggregation in Trauma Patients
Authors: JOHNSON ROBERT A , JOHNSON FRUZSINA K , DURANTE WILLIAM , STEWART RONALD M 
Published: June 2021

Hemorrhage into body cavities is a common complication from blunt trauma. While it used to be standard practice to clear such a hemoperitoneum, more recently they been left untreated due to various concerns with patient stability.ObjectiveDetermine if hemoperitoneum elevates carbon monoxide production and impairs platelet aggregation in trauma patients.MethodsMale patients with verified hemoperitoneum were enrolled along with non‐hemoperitoneum head injury controls. Three days after admission, whole patient carbon monoxide excretion was measured via solid‐phase gas chromatography. A blood sample was drawn to evaluate collagen‐ and thrombin‐induced aggregation.ResultsThree days after injury, patients with hemoperitoneum displayed higher carbon monoxide excretion (0.54±0.10 vs 0.96±0.11 μmol/Kg per hr, control vs hemoperitoneum, P<0.05), and carboxyhemoglobin levels 24% higher than the non‐hemoperitoneum controls. Patients with hemoperitoneum also displayed decreased amplitude of both collagen and thrombin activated platelet aggregation (−23 and − 34%, respectively).ConclusionsAbdominal blood drives endogenous carbon monoxide formation and interferes with hemostatic processes, so inhibitors of carbon monoxide formation may potentially serve as a therapeutic to stabilize affected patients. Supported by grants Department of Army #W81XWH‐07‐1‐0717 (RAJ and RMS), AHA 0865241F (FKJ) and NIH HL064577 (RAJ).
Variations in the density of blood during hemorrhage
Authors: Nunez Fiesky A. , Kislukin V. , Thurmalla N. , Krivitski N. , Callahan M. F. , Smith T. L. 
Published: June 2021

It is known that hematocrit of the whole body (Htb) and venous or systemic hematocrit (Ht1) are different. The cell factor(ratio of whole body to venous Hct) F_c= Htb/Ht1. is around 0.85. Thus one can expect a drop in blood density during blood loss. Since the delivery of O2 (DO2) is proportional to cardiac output x Ht1; the variation of F_c reflects both the redistribution of (a) blood volume toward central circulation, to increase venous return and (b) RBC toward central circulation for the partially restoration of Ht1, the variation/stability of F_c could be a mechanism for compensation of variations of DO2.The aim of this study is to present a method of estimation of Htb/Ht1 during blood loss and to analyze variation of Htb/Ht1 during this challenge.Male Sprague‐Dawley rats (n=55) were hemorrhaged in 3–4 steps with 7 ml/kg body weight withdrawal of blood at each step. An arterio‐venous extracorporeal catheter (priming volume 0.8ml) was connected the carotid artery and jugular vein. Clamp on transit time sensors, TS450 flowmeter and an automatic algorithm (Transonic Systems Inc.) were used to calculate the cardiac output and blood volumes such as central blood volume and actively circulating blood volume.ResultsThe drop in blood density is proportional to F_cell and inversely proportional to the circulating blood volume. A linear drop in density during first and second withdrawals indicates the constancy of F_cell. After completion of the blood withdrawal the Htb/Ht1 was on average, slightly elevated (7% +/−6%), possibly due to the starting of refilling of intravascular volume.
Effects of Commonly Used Chinese Herbal Medicines and Electroacupuncture on Experimental Myocardial Infarct Size
Authors: Dow Joan Stephanie , Painovich Jeannette , Hale Sharon L , Longhurst John C , Tjen-A-Looi Stephanie , Kloner Robert A 
Published: June 2021

BackgroundWe hypothesized that herbal therapy or electroacupuncture (EA) would reduce infarct size and ischemia‐reperfusion induced cardiac arrhythmias.MethodsAn anesthetized rat model of proximal left coronary artery occlusion (30 min) and reperfusion (180 min) was used. Infarct size (IS; triphenyltetrazolium chloride) and ischemic risk zone (blue dye technique) were assessed. In Protocol 1 rats received either saline, Dan Shen (DS) or DS+Jiangxiang (JX), starting 30 minutes before coronary occlusion. In Protocol 2, rats were either untreated, received static needle placement or EA at the PC5 and 6 acupuncture points of the forearm starting 5 minutes before occlusion.ResultsNeither treatment, herbal or EA, reduced IS expressed as a fraction of the ischemic risk zone or altered hemodynamics. Protocol 1: 0.43±0.06 in controls, 0.39±0.05 in DS and 0.42±0.04 in JX; Protocol 2: control (0.38±0.04), static needle (0.47±0.4) and EA (0.32±0.05) (p=NS). In a separate study EA failed to reduce ventricular tachycardia and VPB's. Results may be related to the absence of hemodynamic effects, a major factor underlying the reduction of experimental myocardial ischemia during EA.ConclusionOur studies do not suggest a cardioprotective effect of DS or JX or EA in experimental myocardial ischemia/reperfusion, in the absence of any significant changes in myocardial oxygen demand.
Aerobic Exercise Training Partially Reverses Inward Hypertrophic Coronary Arteriole Remodeling in Type 2 Diabetic db/db Mice
Authors: Trask Aaron J. , Delbin Maria A. , Katz Paige S. , Zanesco Angelina , Lucchesi Pamela A. 
Published: June 2021

The aim of this study was to determine whether aerobic exercise training improves impaired coronary arteriole remodeling in type 2 diabetic db/db mice. Eight wk old male mice were divided into: control sedentary (Db/db), diabetic sedentary (db/db), and diabetic trained (db/db‐TR). Exercise training (ET) was performed on a mouse treadmill for 5 days/wk, 60 min/day, at a speed of 9–10 m/min, 0% grade without electric stimulation for 8 wks. Coronary arterioles were mounted on a pressure myograph to measure wall thickness and diameters over a range of pressures (0–125 mmHg). Coronary arterioles isolated from db/db mice exhibited decreased luminal diameter (Db/db: 119 ± 6 μm vs. db/db: 102 ± 5 μm p < 0.05) with thicker microvascular walls (Db/db: 7.0 ± 0.2 μm vs. db/db: 9.1 ± 0.6 μm p < 0.01), which significantly increased the wall:lumen ratio (Db/db: 6.2 ± 0.4 vs. db/db: 8.8 ± 0.6, p < 0.01). Compared to db/db mice, coronary arterioles isolated from db/db‐ TR mice had similar internal diameter (109 ± 6 μm, p > 0.05) and wall thickness (7.5 ± 0.5 μm, p = 0.14), while wall:lumen ratio (6.8 ± 0.2 μm, p < 0.05) and growth index (db/db: 22.8 vs. db/db‐TR: 5.8, % of Db/db) were reduced. External diameters were not different among groups. These data suggest that aerobic exercise training can mitigate inward hypertrophic remodeling observed in coronary arterioles of type 2 diabetic mice.Support: NIH T32HL098039 to AJT; NIH HL056046 and NCH to PAL.