bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiological properties of YM‐244769, a new and selective NCX blocker, in heart
Authors: Watanabe Yasuhide , Kita Satomi , Iwamoto Takahiro 
Published: June 2021

A selective Na+/Ca2+ exchange (NCX) inhibitor would be very useful for studying both the physiological roles of NCX and a new drug therapy for cardiovascular diseases. In the present study, we examined electrophysiological properties of YM‐244769, a novel benzyloxyphenyl NCX inhibitor, in mammalian heart. NCX currents (INCX) were measured in single cardiac ventricular myocytes of guinea pig by using the whole‐cell voltage‐clamp technique. YM‐244769 suppressed the bi‐directional INCX in a concentration‐dependent manner (0.01–3uM). The IC50 values of YM‐244769 for the bi‐directional outward and inward INCX were both about 0.1uM. YM‐244769 suppressed the uni‐directional outward INCX (Ca2+ entry mode) with the IC50 value of 0.05 uM. In contrast, 10 uM YM‐244769 inhibited it only by about 50%. At 5 mM intracellular Na+ concentration, YM‐244769 suppressed INCX more potentially than it did at 0 mM [Na+]i. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM‐244769. On the other hand, YM‐244769 (1–10uM) did not affect the other membrane currents; INa, ICa, IK1, ISS, Ito and IOAG. YM‐244769 (0.3–3uM) suppressed hypoxia/reoxygeneration‐induced Ca2+ overload.YM‐244769 inhibits the Ca2+ entry mode of NCX more potently than the Ca2+ exit mode in cardiac myocytes. YM‐244769 is a representative NCX inhibitor against the Ca2+ entry mode.
Targeting Potassium Channels On Fibroblast‐like Synoviocytes For The Treatment Of Pristane Induced Arthritis In A Rat Model
Authors: Hu Xueyou , Tajhya Rajeev , Laragione Teresin , Huq Redwan , Koshy Shyny , Khan Fatima , Gulko Percio , Beeton Christine 
Published: June 2021

Targeting Potassium Channels On Fibroblast‐like Synoviocytes For The Treatment Of Pristane Induced Arthritis In A Rat Model Rheumatoid arthritis (RA) is a chronic disease that leads to inflammation of the joints and other organs. Fibroblast‐like synoviocytes (FLS) play an important role in the pathogenesis of RA. We have previously identified and defined the roles of the major functional K+ channels KCa1.1 channels (BK, Maxi‐K, slo1) expressed at the plasma membrane of FLS isolated from patients with RA (RA‐FLS). In the present study, we used RT‐PCR, western blotting, immunocytochemistry, and patch‐clamp electrophysiology to identify KCa1.1 channels as the major functional K+ channels expressed by FLS isolated from rats with pristane‐induced arthritis (PIA), an animal model for RA. Blocking KCa1.1 channels inhibited the proliferation of these cells and their ability to produce MMP‐2 without inducing cytotoxicity. In keeping with these results, blocking KCa1.1 channels also inhibited the invasion of RA‐FLS in Matrigel assays. Furthermore, a KCa1.1 blocker, injected every other day after onset of PIA clinical signs, stopped disease progression. Our findings demonstrated that KCa1.1 channels on fibroblast‐like synoviocytes are promising therapeutic targets for the treatment of RA.This study is supported by funding from Baylor College of Medicine and the NIH (AI084981).
Effects of maternal milk lactoferrin supplementation on neurodevelopment and neuroprotection
Authors: Wang Bing , Larvaron Pierre , Somm Emmanuel , Sizonenko Stéphane 
Published: June 2021

BackgroundLactoferrin (Lf), an iron‐binding glycoprotein containing terminal sialic acid residues, is secreted in milk. Lf is synthesized in brains of both humans suffering from Alzheimer's dementia, and in the mouse model of Parkinson's disease, suggesting that Lf may play a role in neurodegenerative diseases.ObjectiveTo investigate the neuroprotective effects of Lf in rats following prenatal exposure to dexamethasone (DEX) by 1H‐MRS and hippocampal gene expression profiling.MethodIntrauterine growth restriction (IUGR) in rat pups was induced by maternal exposure to DEX supplemented with Lf (1g/kg b.w./day) during gestation and lactation. Neurochemical profiles of hippocampus (HC) and cortex (C) were determined in vivo by 1H‐MRS at 9.4 T, and selected gene expression in hippocampus at postnatal day 7.ResultsDEX in the rat model showed a significant decrease in the concentration of NAA‐NAAG and Glu‐Gln, markers of neuronal integrity and function, in the HC and C. This confirmed the altered brain development after DEX exposure and revealed the potential protective effect of Lf given to gestational and lactating dams in the rat model of prenatal exposure to adverse conditions. DEX‐induced transcriptional changes in BDNF and DMT1, normalized with maternal bLf supplementation.Conclusion: Maternal milk Lf supplementation has a protective effect for neurodevelopment delayed IUGR in the rat model.
Wnt Signaling Mediates De‐differentiation of Endothelial Cells during Neovascularization
Authors: Kohler Erin , Baruah Jugajyoti , Azar Dimitry T , Chang Robert , Malik Asrar B , Wary Kishore K 
Published: June 2021

RATIONALEThe ability to induce de‐differentiation of resident cells in situ at the site of injury or ischemic tissues may be a useful approach for reparative and regenerative medicine. To address this possibility, here we test the capacity of 6‐bromoindirubin‐3′‐oxime (BIO) to induce neovascularization by inducing a transcriptional program centering the NANOG gene networks.RESULTSBIO not only induced interaction of β‐catenin with NANOG, but also increased the expression of mesenchymal and hemangioblastic cell markers NANOG, VEGFR2, BRACHYURY, and CD133, while decreasing mature EC markers CD31 (PECAM‐1) and von Willibrand Factor (vWF). Increased expression of these molecules induced mesenchymal/stem‐like cellular phenotypes and increased neovascularization in Matrigel and in Corneal neovascularization assays. Furthermore, BIO induced asymmetric cell division in these cells, a hallmark of stem cell selfrenewal. In contrast, NANOG knockdown inhibited the ability of BIO treated ECs to divide asymmetrically, to form cellular aggregates, and to undergo angiogenesis.CONCLUSIONThese findings, for the first time, demonstrate the ability of BIO to induce dedifferentiation of ECs into primitive cells in relation to neovascularization by up‐regulating the transcriptional network centering the NANOG gene.Supported by NIH (R01HL079356), AHA, and T32HL072742 NIH training grants.
Mechanical Circulatory Unloading Promotes Proteins Synthesis and Maintains Leucine Oxidation
Authors: Kajimoto Masaki , O'Kelly Priddy Colleen M. , Ledee Dolena R. , Bouchard Bertrand , Isern Nancy , Olson Aaron K. , Des Rosiers Christine , Portman Michael A. 
Published: June 2021

Mechanical ventricular unloading by arterial‐venous extracorporeal membrane oxygenation (ECMO) serves as a bridge to recovery in infants with severe acute heart failure. The influence of mechanical circulatory support on protein synthesis and degradation is unknown. We tested the hypothesis: ECMO induces reductions in myocardial protein synthesis and promotes increased amino acid oxidation. Anesthetized immature swine (n=20) received intracoronary infusion of 13C6, 15N L‐leucine alone or with 2‐13C pyruvate after 8 hours of loading (LOAD) or ECMO. Leucine incorporation into protein and contribution to the citric acid cycle (CAC) relative to pyruvate was determined using 13C‐magnetic resonance spectroscopy and GCMS. ECMO increased the protein fractional synthesis rate (0.91%±0.04% vs. 0.63%±0.10%, p<0.06), but did not alter leucine oxidation relative to pyruvate. ECMO also increased mTOR phosphorylation (by immunoblot) and decreased eukaryotic‐Elongation factor‐2 phosphorylation.ConclusionsMechanical unloading in the form of ECMO enhances protein synthesis without reducing amino acid contribution of acetyl‐CoA to the CAC. The protein synthesis occurs with activation of the mTOR pathway. These data suggest that atrophy induced by clinical mechanical circulatory support and ventricular unloading is caused by accelerated protein degradation.
Increased fat and simple carbohydrate consumption results in obese prepubertal pigs without an increase in body weight
Authors: Reeves H.F. , van Eyk G.R. , Seelenbinder K.M. , Price K.L. , Scheffler T.L. , Gerrard D.E. , Scheffler J.M. , Escobar J. 
Published: June 2021

The objective was to determine how carbohydrate (CHO) source affects body adiposity, intravenous glucose tolerance (IVGT) and insulin levels in female prepubertal pigs. Pigs (28‐d‐old) were used in an 8‐wk trial. Diets were Control or high‐fat (HF), which was further divided into containing complex (Corn) or simple CHO (SC, Glucose or Fructose). Control pigs were pair‐fed to HF pigs resulting in similar weight gain and final body weight across treatments (P=0.81). Compared to Controls, metabolizable energy intakes were higher for HF (37%, P<0.001) and SC (14%, P<0.03) diets. Plasma cholesterol was higher (P<0.02) in pigs fed Corn and Fructose compared to those fed Glucose or Control diets. Ultrasound backfat depth, an indicator of body adiposity, was 84% higher (P<0.001) in HF, and SC tended to increase fat (P=0.11). HF intake increased (P<0.001) fasting blood glucose levels but lowered insulin, HOMA‐B, and HOMA‐IR (P<0.01). SC intake tended to reduce (P=0.08) fasting insulin and lowered HOMA‐B and HOMA‐IR (P<0.05). Glucose area under the curve (AUC) was higher (P<0.05) in HF and SC pigs compared to Control, but insulin AUC was not different (P=0.14) across all treatment combinations. No differences between Glucose and Fructose were found for any measured parameter. Consumption of SC increases body adiposity and alters glucose homeostasis without changes in weight gain.Grant Funding Source : College of Agriculture and Life Sciences
Flow‐Mediated Dilation is Attenuated in Young Patients with Cystic Fibrosis
Authors: Harris Ryan A , Poore Spencer , Berry Breana , Eidson Dabney , Pollock Jennifer S , McKie Kathleen T 
Published: June 2021

Cystic fibrosis (CF) is a fatal genetic disorder that affects the lungs as well as multiple biological systems. This study sought to determine if endothelial function, measured by the flow‐mediated dilation (FMD) test, was lower in patients with CF compared to controls. 15 patients with CF and 15 demographically matched controls participated in this study. Overnight fasting blood samples were taken and FMD and spirometry were performed. No differences in age, height, or BMI were observed between patients with CF and controls (all p>0.05). Although lung function was in the normal range, patients with CF had lower FEV1 when compared to healthy controls (92.8±15 vs. 104.5±11 % predicted). In addition, brachial artery FMD was lower in patients with CF compared to controls (5.0±2.7 vs. 7.6±3.1%; p=0.02) which was accompanied by a slightly higher plasma concentration of 8‐ isoprostane (16±2 vs. 12±1 ng/ml; p=0.20) and NOx (48±5 vs. 35±4 uM; p=0.06) and a lower total antioxidant capacity (1.29±0.11 vs. 1.42±0.08 mM; p=0.38) compared to controls. These data indicate that young patients with cystic fibrosis have impaired endothelial function that precedes the decline in pulmonary function. Systemic oxidative stress and inflammation may be a contributor; however, more subjects are needed to elucidate this mechanism.Supported in part by the American Heart Association (R.A.H) and Child Health Discovery Institute (R.A.H).
The Influence Of PKCδActivity On RhoA Interaction With Its Effector Proteins
Authors: Chichger Havovi , Duong Huetran , Harrington Elizabeth O 
Published: June 2021

The balance of RhoA activation is vital in maintaining endothelial function in part due to its role in cell contraction, a function which regulates vascular permeability. Previous studies have implicated PKCδ activity in the regulation of endothelial barrier function via modulation of RhoA activity. To understand the relationship between PKCδ and RhoA in the pulmonary endothelium, we used co‐precipitation experiments to identify Rho effectors that bind RhoA in the presence and absence of the PKCδ inhibitor, rottlerin.We noted PKCδ binding with both constitutively inactive, RhoAG17A, as well as the constitutively active RhoAQ63L, forms of RhoA. Chemical inhibition of PKCδ resulted in increased PKCδ binding to RhoAG17A but decreased PKCδ binding to RhoAQ63L. Altered binding of RhoAQ63L and RhoAG17A with p190RhoGAP and p115RhoGEF, respectively, was observed upon PKCδ inhibition. Using electric cell‐substrate impedance sensing (ECIS) system, we noted that similar to PKCδ inhibition, Rho kinase inhibition with Y27632 promoted endothelial barrier dysfunction.The data demonstrates that PKCδ influences RhoA activity in pulmonary endothelial cells and the decline in PKCδ or Rho kinase signaling correlated with dysfunction of the endothelial barrier. We propose that PKCδ functions as a regulator of vascular permeability and thus presents an interesting target in the regulation of the pulmonary endothelium.
Acute inhibition but not chronic deficiency of G protein‐coupled estrogen receptor reduces bioactivity of nitric oxide
Authors: Meyer Matthias R. , Field Angela S. , Barton Matthias , Prossnitz Eric R. 
Published: June 2021

The transmembrane G protein‐coupled estrogen receptor (GPER) has been implicated in rapid vascular signaling. Whether endogenous GPER affects bioactivity of nitric oxide (NO) is unknown. We studied gene expression of endothelial NO synthase (eNOS), basal NO bioactivity, and stimulated NO release in the aorta of GPER+/+ and GPER−/− mice (3 mo) isolated for recording of isometric tension. We also determined acute effects of the GPER‐selective antagonist G15 on NO bioactivity. Vascular eNOS gene expression was analyzed by qPCR. Basal NO bioactivity was calculated as the difference in contraction to phenylephrine (PE, 300 nmol/L) in the absence and presence of the NOS inhibitor L‐NAME (300 μmol/L), and receptor‐mediated NO release to acetylcholine (ACh, 0.1 nmol/L – 0.1 μmol/L) was induced in PE‐precontracted rings. Chronic GPER deficiency had no effect on eNOS gene expression, basal NO bioactivity, or ACh‐stimulated, NO‐mediated relaxation. In contrast, acute inhibition of GPER by G15 reduced basal NO bioactivity by 34% (38.3±5.7% vs. 57.7±5.2%, n=4–6, P<0.05 vs. vehicle) and inhibited relaxation to ACh‐stimulated NO release by 18% (−60.7±3.5% vs. −74.4±2.5%; AUC 90±11 vs. 133±9 units; n=5–6, P<0.05 vs. vehicle) in GPER+/+ mice. These data demonstrate that acute inhibition of GPER reduces basal NO bioactivity and inhibits stimulated NO release. In contrast, the NO pathway appears to be unaffected by chronic GPER deficiency.Supported by Swiss National Science Foundation (SNSF) grant PBZHP3‐135874.
Determination of actively circulating volume (ACV) by injection of normal saline
Authors: Nunez Fiesky A. , Kislukin V. , Thurmalla N. , Krivitski N. , Smith T. L. , Callahan M. F. 
Published: June 2021

Examination of the indicator concentration curves after rapid injection of normal saline reveals the existence of transient damped oscillations followed by a new, relatively stable level of arterial blood density. We hypothesized that the variation in density could be used to estimate ACV. To address this issue we analyzed the variation of arterial hematocrit (Ht1) during the injection/infusion of 0.9% NaCl; and performed experiments to answer the question: what is the rate of the restoration of blood density, in other words, what is the rate of leakage of injected normal saline from active circulation if (a) the blood volume is elevated up to 50% of expected and (b) if blood is withdrawn up to 30% of expected BV.Male SD rats (n=15) were anesthetized and received an extracorporeal A‐V loop connecting the carotid artery and the jugular vein with a controlled flow rate (8ml/min). Transit time clamp‐on sensors, TS450 flowmeter and an automatic algorithm (Transonic Systems Inc.) were used to calculate the cardiac output and central and actively circulating blood volume following injection of isotonic saline (0.3ml) into the venous limb of the AV loop. Hemorrhage was done by controlled blood withdrawals(~30 ml/kg in 3–4 steps). Increase of ACV was performed by series of 15–20 injections of 0.5–1 ml of normal saline.Results(1) Analysis of Ht1 variations reveals if Htb/Ht1 is constant then 0.9% NaCl is an indicator for ACV determination; (2) The rate of leakage of injected normal saline from active circulation is ~ 1–3%/min in normal or hypovolemic states and is up to 10%/min if ACV is elevated up to 30% of expected baseline.
Continuous Use of Intrathoracic Pressure Regulation Device Improved Cardiac Output in Porcine Peritonitis
Authors: Goldfarb Roy David , Jaffe J. Douglas , Torjman Marc C , Mitrev Ludmil , Jasti Purnachandra , Knob Christopher , Metzger Anja , Lurie Keith , Parrillo Joseph E. , Dellinger R. Phillip 
Published: June 2021

Septic shock initiates multiple pathophysiologic pathways manifesting characterized by reduced cardiac output. We tested an Intrathoracic Pressure Regulator (IPR) a device which decreases intrathoracic pressure during passive exhalation creating more negative intrathoracic pressure enhancing venous return and cardiac output. We hypothesized that continuous IPR therapy would improve cardiac output without fluid resuscitation during porcine peritonitis.Six Yorkshire pigs (30–40kg) were anesthetized with isofluorane, intubated, mechanically ventilated, instrumented with a Swan‐ Ganz and a femoral artery catheter. Animals were assigned to a treatment or control group. After a basal period, peritonitis was induced by implanting a fibrin clot containing 4×109 cfu·kg−1 E. coli O11.B4. At 2 hours IPR was applied for 4 hrs or until the animal met euthanasia criteria. The primary outcome measurement was cardiac index.Continuous IPR augmented cardiac index and mean arterial blood pressure for duration therapy, becoming larger as time increased while pulmonary vascular resistance declined. This study demonstrated that IPR treatment for peritonitis caused significant cardiovascular support in this model. Further studies are needed to determine the potential clinical benefit of this non‐invasive circulatory enhancement technology.
Anti‐Inflammatory Effects of ACE Inhibition Persist Following Withdrawal of Treatment
Authors: Hale Taben Mary , Tu Danni , Shahid Wafa , Biwer Lauren A 
Published: June 2021

Transient (2‐wk tx + 2‐wk washout) angiotensin converting enzyme (ACE) inhibition induces persistent changes that result in a preservation of cardiac function and fewer infiltrating macrophages after 10 days of nitric oxide synthase inhibition (L‐NAME) – despite evidence of infarction. In the present study we investigated whether prior ACE inhibition (enalapril) would yield a modified immune response during L‐NAME‐induced pathological remodeling. We performed a time course analysis of left ventricular (LV) inflammatory cytokines and macrophage infiltration during L‐NAME (L) treatment in SHR that were previously treated with placebo (C+L) or enalapril (E+L) for 2wks followed by 2‐wk washout. L‐NAME equivalently increased arterial pressure, regardless of pre‐treatment. Distinct patterns of cytokine levels were observed in C+L vs E+L. In C+L, but not E+L LV there was an early (day 3) and sustained increase in monocyte chemoattractant protein‐1 and granulocyte macrophage colony stimulating factor that resulted in a significant increase in macrophage infiltration on day 7 of L‐NAME treatment.This is the first evidence that transient pre‐treatment with an ACE inhibitor can produce long‐term changes in L‐NAME‐induced immune responses. Further studies will determine whether this reduced macrophage recruitment will result in attenuation of post‐infarct remodeling.
Impact of Hyperhomocysteinemia on Cardiac Gene Expression in Pregnant Rats
Authors: Song Su , Ojaimi Caroline , Kertowidjojo Elizabeth , Zhang Su Hua , Huang Harer , Kandhi Sharath , Wolin Michael , Hintze Thomas H 
Published: June 2021

Hyperhomocysteinemia (HHcy) causes cardiovascular dysfunction during pregnancy. We have previously shown that HHcy disrupts the regulation of O2 consumption in the heart by lowering NO bioavailability through the generation of superoxide. Presently, we explored the molecular effects of HHcy during pregnancy. Pregnant SD rats were fed with 10g/L methionine in drinking water for 20 days to increase plasma homocysteine (Hcy) (3.0±1.2 to 14.6±8.9 uM). mRNA microarray analysis of left ventricle tissue revealed significant changes in 242 genes (p<0.05, > ±1.5). We grouped differentially expressed genes into different functional categories, and the results showed a wide range of distribution of expression patterns within the functional groups. For example, some cell structure/motility genes were upregulated, including Kruppel‐like factor, histone deacetylase 1, myosin 1b, and ARP2 actin‐related protein 2. We have also seen several oxidative stress‐related genes, such as hypoxia up‐regulated 1 and ischemia related factor up‐regulated. Metabolism genes such as pyruvate dehydrogenase phosphatase isoenzyme 2 and fatty acid transporter 4 were differentially regulated.ConclusionHHcy triggers cardiac gene expression changes during pregnancy, suggesting an underlying mechanism behind the effects of HHcy.
Thyroid hormone preserves myocytes in the border zone of myocardial Infarction
Authors: Chen Yuefeng , Youmans Steven , Weltman Nathan Y. , Li Xiang , Crause David , Gerdes Anthony Martin 
Published: June 2021

IntroductionThyroid hormone (TH) improves left ventricular (LV) remodeling and function after myocardial infarction (MI); however, the cellular basis is unknown.MethodsMI was produced by ligation of the LAD in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3mg, 60 days release, implanted subcutaneously immediately following MI). Each group was further divided into two subgroups (n=9 per subgroup) for myocytes isolation and whole heart tissues collection eight weeks after surgery.ResultsMI resulted in LV chamber dilatation and functional impairment, with LV myocyte lengthening. T4 treatment after MI improved LV function, increased LV weight by 37%, increased LV myocyte volume and cross‐sectional area (CSA) by 13%, and increased non‐infarcted tissue area by 41%, but did not change the infarct perimeter or LV dimension (Table 1). The increase in LV myocyte volume accounted for only 1/3 of the increase in non‐infarcted tissue area, indicating an increased number of surviving myocytes accounted for the remaining portion. Based on our previously published paper, T4 treatment might help to preserve myocytes in the border zone after MI via its anti‐apoptotic effect.ConclusionsThese results suggest T4 treatment after MI can improve LV myocyte remodeling and preserve myocytes in the border zone.