bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemodynamic and bioenergetics of hearts from obese adult mice overfed during early life
Authors: Vieira Anatalia Kutianski , de Mattos Ana Marcondes , Neves Fabiana Alves , Bernardo Amélia Faustino , Cortez Erika Costa , de Souza Larissa Ramos , Miranda Glauciane Lacerda , de Melo Soares dos Santos Vivian , de Souza Rodrigues‐Cunha Alessandra Cordeiro , Garcia‐Souza Érica Patrícia , Sichieri Rosely , Moura Anibal Sanchez 
Published: June 2021

In this study we examined heart hemodynamic and metabolism of adult obese mice overfed during lactation. Heart left ventricle from obese (OG) and control (CG) groups were studied. Analysis of key proteins of cardiomyocyte metabolism and bioenergetics were associated to heart hemodynamic by the Langendorff System and high‐resolution respirometry by Oroboros 2k‐Oxygraph during Baseline (CGBL, OGBL) and Ischemia/Reperfusion (CGIR, OGIR) conditions. OG showed a significant increase in total body mass (p<0,0001), epididymal fat (p=0,0018), retroperitoneal fat (p=0,0046) and glycemia (p=0,0471) when compared with CG. Hemodynamic showed lower Max dp/dt (p=0,0007) and heart frequency (BPM) (p=0,0178) in OGIR when compared to OGBL; higher Tau (relaxation time) (p=0,001) in OGIR compared to CGIR and OGLB. Respiratory control ratio (RCR) of isolated heart fibers of OGBL was decreased to fatty acid and carbohydrate oxidation, OGIR only to fatty acid. There were no difference in O©ü consumption of OGBL and OGIR. Hearts from OGBL and OGIR presented lower content of phosphoAKT and IR when compared to CG. We suggested that early life overnutrition induces permanent alterations of cardiac activity and that this process is associated with proteins of the insulin signaling cascade and mitochondrial energy metabolism.Supported by FAPERJ (E‐26/110.578/2009)
Regenerative cerebral arteriogenesis is induced by GM‐CSF and inhibited by anti‐inflammatory cardiovascular medications
Authors: Persson Anja Bondke , Duelsner André , Gatzke Nora , Buschmann Ivo R. 
Published: June 2021

Restoration of blood flow in case of stenotic brain‐supplying arteries relies on restoration of arterial inflow, achieved by an outgrowth of preexistent arterioles (arteriogenesis) and depends on monocyte migration into the vesel wall. It was assumed that a stimulation of monocytic function induces collateral growth, while anti‐inflammatory substances might interfere negatively.In two animal models of cerebral hypoperfusion (3‐vessel occlusion/rats, common carotid artery occlusion/mice), administration of the pro‐arteriogenic Granulocyte Colony‐ Stimulating Factor (40ug/kg) augmented angiographic collateral diameters and restored cerebrovascular reserve capacities (CVRC) (20+ 8%, cont. −14+14%). Acetylsalicylic acid (ASA), used in patients at risk for arterial stenosis, interfered with (a) CVRC restoration (1+4%), (b) collateral vessel growth and (c) monocyte migration, while Clopidogrel did not. Current data indicate similar effects for other anti‐inflammatory drugs and other vascular beds, which may explain why their effects on outcomes may fall behind effects on cardiovascular risk factors.Anti‐inflammatory drugs should be used with care in patients with vascular occlusions until large‐scale clinical data on antiarteriogenic effects have been obtained.
Total/HDL cholesterol ratio predicts impaired NO‐dependent vasodilation in human skin
Authors: Dahmus Jessica D. , Craighead Daniel H. , Kenney W. Larry , Alexander Lacy M. 
Published: June 2021

The human cutaneous circulation is a representative vascular bed to assess preclinical systemic microvascular dysfunction. A standardized local heating protocol (0.5°C/30sec) was performed to determine risk factors associated with eNOS‐mediated NO‐dependent vasodilation, as measured by the 42°C plateau in skin blood flow (SkBF). Laser speckle contrast imaging (LSCI), a state‐of‐the‐art method for imaging a larger skin surface area compared to single‐point laser‐Doppler flowmetry was used to measure SkBF. We sought to determine the cardiovascular risk factors most predictive of preclinical impairments in cutaneous microvascular dysfunction in healthy human subjects across a broad range of age, blood pressure, and serum cholesterol (CHOL) concentrations. Subjects included 48 men and women (age: 19–88 yr, body mass index: 19.7–36.2 kg/m2, systolic pressure: 90–150 mmHg, diastolic pressure: 50–96 mmHg, total serum CHOL: 121–321 mg/dl, total/HDL ratio: 1.79–7.47, LDL: 54–199 mg/dl, HbA1C: 5.1–5.9, and fasting blood glucose: 80–114 mg/dl). A stepwise regression analysis was performed to determine the best predictor(s) of NO‐dependent vasodilation. The total/HDL ratio predicted impairments in the NO‐dependent plateau (R=0.27, p = 0.01) response to local heating. Microvascular dysfunction as measured by attenuated eNOS‐mediated vasodilation is associated with adverse cholesterol ratios.R01 AG07004, HL093238, HL089301
Beneficial Effects of Angiotensin (1–7) On Dysfunctional CD34+ Endothelial Progenitor Cells (EPC) from Patients with Heart Failure
Authors: Hazra Sugata , Cole‐Jeffrey Colleen T. , Pepine Carl J , Katovich Michael J , Grant Maria B , Raizada Mohan K 
Published: June 2021

Endothelial dysfunction is well established in heart failure (HF) and thus HF individuals can be benefitted from autologous cell therapy. In HF patients, the numbers of circulating EPCs vary with NYHA stage. We hypothesized that CD34+ EPCs are dysfunctional in heart failure (HF) patients which can be corrected by angiotensin 1–7 (Ang‐(1–7)). Peripheral blood was collected from control (n=10) and NYHA class II‐IV HF patients (n=15). CD34+ cells were enumerated by flow cytometry and were assessed for migratory potential, NO generation, ROS levels with and without Ang1–7. HF patients showed 63% reduction in number of CD34+cells, 60% reduction in BFU‐E, 74% increase in CFU‐GEMM colonies, reduced expression of ACE2, MAS1 and IL‐10 whereas increased expression of TNF‐α and IL‐6 compared to controls. Migratory potential of CD34+ cells in HF patients were reduced by 77%. Additionally, CD34+ cells from class III donors had 44% reduction in NO/ROS ratio due to increased ROS and reduced NO. Ang‐(1–7) treatment improved their migratory response, reduced ROS and increased NO which resulted in a 54% increase in NO/ROS ratio. These data support that CD34+ cells isolated from HF individuals are dysfunctional, with a reduction in number, colony forming ability, migratory potential, NO generation and increased oxidative stress and these dysfunctions can be corrected by Ang‐(1–7), which suggests therapeutic potential of Ang‐(1–7).This work was supported by HL56921
Mechanosensitive activation of ATP‐sensitive K+ channels in native pulmonary epithelium depends on pannexin and connexin hemichannel mediated ATP release
Authors: Richter Katrin , Kiefer Kevin Peter , Lintges Michael , Geissert Lea , Clauss Wolfgang , Fronius Martin 
Published: June 2021

ObjectiveThe pulmonary epithelium (PE) is permanently exposed to mechanical forces (shear force, stretch). There is evidence that distention of PE leads to an activation of ATP‐sensitive K+ (KATP) channels. The aim of this study was to clarify the mechanisms of KATP channel activation and the contribution of hemichannels in particular.MethodsA modified Ussing chamber that enabled the application of hydrostatic pressure (HP) was used to mechanically stimulate native PE derived from Xenopus laevis while the short circuit current (ISC) was recorded. Activation of KATP channels was ascertained by the application of the specific inhibitor HMR 1098. Contribution of hemichannels was investigated by application of connexin (meclofenamic acid) and pannexin (probenecide) inhibitors. Extracellular ATP was determined via a luminescence ATP detection assay.ResultsApical application of HP led to a pressure‐induced current decrease (17.6 ± 2%, P<0.001). This effect was prevented by HMR 1098. The HP‐induced effect was also reversed by the hemichannel inhibitors. Under control conditions (without pharmaca) the HP‐induced effect was accompanied by an increased ATP release which was also inhibited by the hemichannel inhibitors.ConclusionKATP channel activation in response to HP is caused by ATP release through a mechanosensitive activation of connexin and pannexin hemichannels.
The relationship of muscle sympathetic nerve activity to the sympathetically‐mediated thermic effect of food in young healthy subjects
Authors: Matzek Luke James , Miles John , Jensen Michael , Levine James , Joyner Michael , Curry Timothy 
Published: June 2021

The thermic effect of food (TEF) is partially mediated by β‐adrenergic receptors (βAR) and is an important component of daily energy expenditure. Greater sympathetic activity has been associated with decreased BAR responsiveness. We hypothesized that muscle sympathetic nerve activity (MSNA) would be inversely correlated with the βAR component of TEF (TEFβ). We measured MSNA (microneurography) and energy expenditure (EE) (indirect calorimetry) before and for 5 h after a mixed meal (40% daily EE). Measurements were made during systemic βAR blockade with propranolol (BB) and saline (NS) infusion on separate days in 10 healthy subjects (2 female, age 28±2 y, BMI 24.4±0.6 kg/m2). Resting MSNA was 39±3 bursts/100 heartbeats (hb). Within 1 h after the meal, MSNA significantly increased during both NS (12±3 bursts/100 hb) and BB (18±4) but was not significantly different between the two days, (P=0.375). The maximum increase in REE after the meal was 269±29 (NS) and 198±22 (BB) kcal/24 h (P<0.05). TEFβ (TEFβ = AUC TEFNS – AUC TEFBB) was 48±20% of total TEF. TEFβ was positively correlated with resting MSNA (R2=0.70, P<0.05). Contrary to our hypothesis, we found that greater levels of MSNA were associated with greater TEFβ. These results indicated that resting MSNA may be an important contributor to daily energy expenditure. Studies are needed to determine if greater MSNA is associated with a resistance to weight gain.The project described was supported by the Mayo Foundation for Medical Education and Research and NIH Grant Numbers K23 DK82424, P30 DK50456, and UL1 RR024150.
Treatment with sulodexide restores compromised glucose tolerance in diet‐induced obese mice
Authors: Eskens Bart , Vink Hans , VanTeeffelen Jurgen 
Published: June 2021

We showed in a previous study that feeding mice a high‐fat diet (HFD) resulted in an early reduction in endothelial glycocalyx barrier properties in hindlimb muscle microcirculation which was associated with increased blood glucose levels during a glucose tolerance test. In the current study we investigated whether sulodexide (SUL), an endothelial glycocalyx mimetic, could improve glucose tolerance at the early stage of diet‐induced obesity (DIO).C57Bl/6 mice were fed a HFD for 6 weeks (n=12); SUL (0.15 mg/mL) was given in the drinking water in the last two weeks (n=5). After 6 weeks the mice were anesthetized and glucose tolerance was measured by i.p. injection of 1 g/kg glucose and the area under the curve of blood glucose (AUCgluc) and plasma insulin (AUCins) were determined for 90 minutes after glucose injection.While baseline glucose and insulin levels were not affected by the SUL treatment, AUCgluc was significantly lower in the SUL treated mice (242 ± 43 versus 404 ±‐ 43 mmol/L * 90 min). AUCins was not affected by the SUL treatment (2108 ± 431 versus 2952 ± 512 μU/ml * 90 min).The results of the current study suggest that preventing or diminishing endothelial glycocalyx loss may be a promising intervention for improving glucose homeostasis in obesity.Supported by DFN 2006.00.027, and CTMM work package 01C‐104–04‐PREDICCT
Intact colonic K+ secretion in KCNMB2 knockout mice
Authors: Larsen Casper Kornbech , Praetorius Helle Anette , Leipziger Jens 
Published: June 2021

Colonic K+ secretion occurs via the pump‐leak mechanism; K+ is taken up from the basolateral side via the Na+/K+ pump and NKCC1 and leaves the cells via apical K+ channels. The BK channel has been identified as the relevant K+ channel involved in K+ secretion in mammalian distal colon. It consists of 4 α‐subunits (encoded by KCNMA1) and 4 modulatory β‐subunits, of which there are 4 isoforms (KCNMB1–4). Previously, we have shown that the β2‐(KCNMB2) is the only β‐subunit expressed in the murine distal colon and that aldosterone increases the expression of both the α‐ and the β2‐subunit.We hypothesize that upregulation of the β2‐subunit participates in aldosterone‐induced colonic K+ secretion. Here we use a global β2 subunit (KCNMB2) knockout mouse, in which we study distal colonic K+ secretion by open‐circuit recordings in Ussing chamber. The luminal Ba2+‐sensitive short circuit current was taken as measure of BK channel‐mediated electrogenic K+ secretion. Resting K+ secretion was 20.8 μA·cm−2 ± 3.8 and 28.2 μA·cm−2 ± 4.4 in WT and KO tissue, respectively (n=6). We found that apical ATP, known to activate K+ secretion via luminal P2Y receptors, increased colonic K+ secretion to −127.2 μA·cm−2 ± 9.47 (WT) and −73.4 μA·cm−2 ± 4.9 (KO) We report the surprising finding that knockout of the assumed β‐subunit (KCNMB2) of the BK channel leaves resting and ATP‐stimulated K+ secretion intact.Supported by the Lundbeck foundation.
Renin gene expression is regulated by Chicken Ovalbumin Upstream Promoter Transcription Factor II (COUP‐TF II)
Authors: Lachmann Peter , Mayer Sandra , Roeser Marc , Ishii Sumiyashi , Suh Jae Mi , Harlander Sabine , Desch Michael , Brunßen Coy , Morawietz Henning , Tsai Sophia Y. , Tsai Ming‐Jer , Hohenstein Bernd , Hugo Christian , Todorov Vladimir T. 
Published: June 2021

We aimed to investigate the involvement of the nuclear receptor COUP‐TFII in the regulation of renin gene expression.Protein‐DNA binding studies demonstrated that COUP‐TFII binds to the proxDR sequence in the proximal renin promoter. Knockdown of COUP‐TFII in the renin‐producing cell lines As4.1 and Calu‐6 reduced the stimulation of renin mRNA expression by cAMP agonists. The mutation of the proxDR element in renin promoter reporter gene constructs abrogated the inducibility by cAMP. The proxDR sequence was essential for the function of a renin promoter cAMP‐response element. Knockdown of COUP‐TFII or cAMP‐binding protein (CREB) decreased the basal renin gene expression. When CREB was knocked down, the deficiency of COUP‐TFII did not further diminish the renin expression. Mice deficient in COUP‐TFII have lower renin expression than their control strain. Surprisingly, there was no significant difference in both plasma renin concentration and blood pressure between wildtype and COUP‐TFII‐deficient mice. Altogether our data show that COUP‐TFII is involved in the control of renin gene expression. To better characterize the role of COUP‐TFII for the renin production in vivo we are generating mice with selective COUP‐TFII deletion in the renin‐producing cells of the kidney.
Wound healing activity of (−)‐borneol complexed to chitosan bioactive film in rodents
Authors: de Souza Siqueira Barreto Rosana , da Silva Prado Douglas , Galvão Juliana Gouveia , da Cunha Gonsalves Joyce Kelly Marinheiro , de Souza Nunes Rogéria , Albuquerque‐Júnior Ricardo Luiz Cavalcanti , Soares Rosilene Calazans , de Lucca Waldecy , Quintans‐Junior Lucindo 
Published: June 2021

The aim of this study was to investigate the wound healing activity of (−)‐borneol complexed to chitosan film on excision wound model in rats.Excision wound:Sixty rats, Wistar, 250–300 g were anesthetized and an excisional wound was performed. The animals was treated with placebo (inert chitosan bioactive film), (−)‐borneol 0.5% and (−)‐borneol 1%, for 3 and 7 days. The residual wounds were analyzed and removed. The activity of the enzyme myeloperoxidase was analyzed at 3 days. Serial histological sections were obtained and stained by histochemical techniques (Hematoxilin‐Eosin – HE and Sirius red) and immunohistochemical techniques. Experimental protocols were approved by the Animal Care and Use Committee at the Federal University of Sergipe (CEPA#01/2011). The results suggest that the chitosan bioactive film with (−)‐borneol reduced (p < 0.05) wound areas, induced earlier granulation tissue formation and increased cell proliferation when compared to the control group. And the chitosan bioactive film with (−)‐borneol 0.5% and (−)‐ borneol 1% decreased (p < 0.05) the activity of the enzyme myeloperoxidase. It is suggested that (−)‐borneol modulates the wound healing process.
Role of AKAP79 in â1‐Adrenergic receptor resensitization and recycling
Authors: Li xin , Bahouth Suleiman W. 
Published: June 2021

AKAPs (A‐kinase anchoring proteins) have been shown to participate in macromolecular signaling complexes that include protein kinases, phosphodiesterases, ion channels, and also GPCRs. In this study, we examine the role of AKAP79 (also known as AKAP79/150) in the trafficking of β1‐Adrenergic Receptor in vitro in HEK‐293 cells and in neonatal cardiac myocytes derived from AKAP150 homozygous knock out mice.Selective down regulation of AKAP79 in HEK‐293 cells and in rat neonatal cardiac myocytes, inhibited the recycling of the WT β1‐AR in HEK‐293 cells and the reintroduction of siRNA‐resistant AKAP79 rescued the recycling of the agonist‐internalized β1‐AR. Furthermore, in neonatal ventricular myocytes derived from AKAP150−/− mice or from AKAP150+/+ the β1‐AR was internalized, but did not recycle in myocytes from AKAP150−/− mice. The recycling of the β1‐AR was rescued by AKAP79, indicating that AKAP79 was required for the recycling of the β1‐AR to occur and shows that these studies across a spectrum of different cells yielded the same result. In addition we tested the effect of three different truncated mutants of AKAP79, namely AKAP79 [1–360] (ΔPKA‐binding site), AKAP79 [115–412] (Δmembrane and PKC binding domains] and AKAP79 [ΔPIX] (Δcalcineurin‐binding domain] their ability to recapitulate the effect of full‐length AKAP79 on recycling of the β1‐AR in AKAP79‐knock down cells. Immunopricipitation data showed that the interaction between the mutants and β1‐AR remained unchanged. However, none of these AKAP79 mutants was capable of rescuing the recycling of the β1‐AR in HEK‐cells, indicating the entire molecule of AKAP79/150 was required for this effect. Funded by NIH HL‐085848.
Mouse Flower‐like (mFl), a membrane protein involved in endocytosis?
Authors: Mannebach‐Götz Stefanie , Frohnweiler Katja , Wissenbach Ulrich , Flockerzi Veit 
Published: June 2021

Recently, a novel membrane protein in Drosophila melanogaster was shown to be localized in presynaptic vesicles. It appears to mediate a Ca influx after vesicle fusion with the plasma membrane. Disruption of the corresponding gene leads to endocytic defects in flies. Apparently, this protein could serve as a Ca channel required for endocytosis. In addition it may determine clonal selection by forcing cells to undergo apoptosis.We have identified a protein in mouse which shares 26,3% amino acid sequence identity with the fly protein and which we call mouse Flower‐like or mFl. The mFl protein is encoded by a gene on chromosome 2. In addition to the “full length” mFl protein (mFlA), 3 shorter variants were identified (mFlB, D, E). After expression of the His‐SUMO‐mFlA‐fusion protein in E. coli and removal of the tag the purified protein was used for immunization of rabbits. The anti‐mFl antibody recognizes mFl variants in brain, pancreas, kidney, thymus, liver, lung and colon. Using RT‐PCR mFlA transcripts could be identified additionally in heart, spleen and mast cells.To analyze mFl functions we are generating mFl deficient mouse lines. The targeting strategy for conditional inactivation of the gene offers the option to study the cellular localization of mFl. Currently we have 11 heterozygous mFl transgenic mice; they will be crossed with Cre or Flp expressing mice to get mFl deficient animals.
Alternative polyadenylation mediated shortening of the Hsp70.3 3′UTR increases polyribosome loading of the mRNA transcript
Authors: Gabanic Andrew , Paulding Waltke , Roessler Anne , Luther Kristin , Smith Leah , McGuinness Michael , Tranter Michael 
Published: June 2021

IntroductionHeat shock protein 70.3 (Hsp70.3) expression is increased in response to cellular stress and plays a cytoprotective role, including a cardioprotective role in the heart against ischemia/reperfusion (I/R) injury. Recent work from our lab shows that Hsp70.3 expression following I/R is controlled through alternative polyadenylation (APA). Truncation of the 3′UTR removes potential regulatory sequences and is observed concomitant with upregulation of Hsp70.3 expression. Herein, we investigated the hypothesis that APA truncation of the 3′UTR enhances polysome loading of the Hsp70.3 transcript.MethodsSucrose gradient ultracentrifugation was used to isolate polysome bound mRNA from HL‐1 cardiac myocyte cells subjected to control (long 3′UTR) or a 1 hr heat shock (HS; short 3′UTR).ResultsCells subjected to HS for one hour showed a decrease in the total amount of polysome loaded mRNA. The Hsp70.3 transcript found in the polysome dense fractions existed as a higher ratio of the APA truncated short 3′UTR, thus supporting our hypothesis that APA truncation of the Hsp70.3 3′UTR increases polysome loading.Our results provide an enhanced understanding of APA on the regulation of Hsp70.3 and will have a significant impact in understating the regulation of cardiac gene regulation after I/R injury.This work was partially funded by a University of Cincinnati Provost Pilot Research Project grant (MT).
A novel redox‐based epigenetic signaling mechanism for opioids
Authors: TRIVEDI MALAV , Hodgson Nate , Shah Jayni , Deth Richard 
Published: June 2021

ObjectiveTo study the involvement of different opioid receptors and downstream signaling pathways for maintaining redox homeostasis via epigenetic regulation of gene expression.Methods and ResultsWe investigated acute and long‐term effects of selected opioid drugs on EAAT3‐mediated transport of cysteine, a precursor for glutathione (GSH) synthesis. Subsequent changes in GSH/GSSG and methylation capacity were measured. Mechanistic investigations suggested temporal involvement of different G‐proteins and downstream signaling protein‐kinases. 5‐Methyl cytosine levels and global DNA methylation levels were also measured. Genome‐wide mRNA expression microarray analysis revealed temporal effects of morphine on transcription. qRT‐PCR analysis showed changes in mRNA levels of enzymes and transporters involved in GSH synthesis, methylation and transulfuration pathways. Redox and methylation responses upon removal of opioids after a prolonged exposure (in‐vitro washout) was also observed.Our findings suggest a novel mechanism for opioid drugs, involving changes in redox status and global DNA methylation mediated by multiple downstream signaling pathways. This mechanism may contribute to opioid drug abuse, tolerance, withdrawal phenomenon and may lead to development of therapeutic interventions.Funding Agency: National Institute of Drug Abuse.