bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteonectin protects against adverse cardiac inflammation during viral myocarditis
Authors: Papageorgiou Anna , Rienks Marieke , Vanhoutte Davy , Verhesen Wouter , Carai Paolo , Vandendriessche Thierry , Chuah Marinee , Heymans Stephane 
Published: June 2021

Viral myocarditis is inflammation of the heart muscle as a consequence of infection by common viruses and outcomes for patients range from complete recovery to fatal dilated cardiomyopathy. We investigated the role of the matricellular protein Osteonectin (SPARC) in mitigating the cardiac injury during viral myocarditis.SPARC mRNA and protein expression was induced in the mouse model of viral myocarditis at 7 and 11 days respectively. Under these conditions, SPARC co‐localized with CD‐3‐lymphocytes and VCAM‐endothelial cells. SPARC‐null mice and their wild type (WT) littermates were subjected to human coxsackie‐virusB3 (CVB3)‐induced myocarditis and the absence of SPARC significantly increased cardiac inflammation and mortality as compared to WT mice. We found that SPARC null mice had increased levels of Ly6G+ and Ly6C+ myeloid cells and fewer CD4+ lymphocytes in the heart during viral infection. Importantly, adenoviral overexpression of SPARC in WT animals resulted in improved cardiac function after viral injury as compared to control vector (fractional shortening was 28,2%±0,6 vs 21,2%±0,8 respectively). Collectively these data indicate a role for SPARC in endothelial cell function, leukocyte function and cardiomyocyte contractility. This multifunctional glycoprotein represents an exciting novel target in the treatment of inflammatory heart disease.
A complex interplay between NO, EDHFs, and KIR channels in cutaneous active vasodilation
Authors: Brunt Vienna E , Fujii Naoto , Minson Christopher T 
Published: June 2021

EDHFs contribute largely to skin local hyperemia. We sought to determine if they also contribute to active vasodilation (AVD) during whole‐body heating. Skin blood flow was measured at 4 sites perfused via microdialysis with 1) Lactated Ringer's, 2) tetraethylammonium (TEA, calcium‐sensitive potassium channel & EDHF inhibitor), 3) L‐NAME (NOS inhibitor), and 4) TEA + L‐NAME. Data is presented as % of max cutaneous vascular conductance. TEA had no effect on AVD (plateau at the end of heat stress: control=55.2±4.6% vs. TEA=63.2±5.2%, p=0.34), indicating EDHFs are not obligatory. L‐NAME attenuated plateau (33.7±5.4%); while TEA+L‐NAME augmented plateau compared to L‐NAME alone (49.7±5.3%, p=0.02 vs. L‐NAME), and did not differ from control (p=0.72). From these data, it appears that combined blockade of EDHFs and NOS forces dilation to occur through other means, possibly through inward‐rectifying potassium (KIR) channels. To test this second hypothesis, we measured AVD at the following sites: 1) Lactated Ringer's, 2) L‐NAME, 3) L‐NAME + TEA, and 4) L‐NAME + TEA + barium chloride (BaCl2, KIR channel inhibitor). The addition of BaCl2 to L‐NAME + TEA reduced plateau to 25.4±6.2% (p=0.01 vs. L‐NAME + TEA), which did not differ from the L‐NAME site (p=0.59). These data combined demonstrate a complex interplay between vasodilatory pathways, with cross talk between NO, EDHFs, and KIR channels.Supported by NIH Grant HL081671
Increased respiratory rhythm and O2 and CO2 chemosensitivity in juvenile rats submitted to perinatal protein undernutrition
Authors: Costa‐Silva João Henrique , Alves José Luiz B. , Nogueira Viviane O. , Oliveira Gerliny B. , Da Silva Glauber S.F. , Wanderley Almir G. , Leandro Carol V.G. 
Published: June 2021

We evaluated the effects of perinatal protein undernutrition on the respiratory pattern and responses to hypercapnia and hypoxia. Pregnant Wistar rats received normoproteic (NP, 17% of protein) or hypoproteic diet (HP, 8% of protein) during gestation and lactation. Male offspring (NP: n=10; HP: n=10) at the 30‐day‐old were evaluated for respiratory frequency (Rf), tidal volume (VT) and ventilation (VE), and ventilatory responses to hypercapnia (10% CO2) and hypoxia (7% O2). At rest, HP rats showed increased Rf (NP: 105.3±3.1 vs. HP: 135.1±2.2 cycles.min−1, P<0.0001) and Ve (NP: 987.4±36.1 vs. HP: 1384.9±57.1 mL.kg− 1.min−1, P<0.0001), but no change in VT. After exposure to hypercapnia, HP showed higher ventilatory responses than NP rats in Rf (NP: 170.5±2.8 vs. E: 181±3.5 cycles.min−1, P=0.02) and Ve (C: 2349.1±111.1 vs. E:2769.8±151.8 mL.kg−1.min−1, P=0.03). Likewise, hypoxia‐induced ventilatory responses were increased in HP rats in Rf (NP: 116.9 ±4.1 n= 5 vs. HP: 146.1±4.4 resp.min−1, p=0.0010), VT (NP: 12.0±0.7 vs HP: 16.5 ±1.2 mL.kg−1, p=0.0135) and Ve (NP: 1449.5 ±114.9 vs. HP: 2454.3 ± 175.0 mL.kg−1.min−1, p=0.0013). Our data suggest that juvenile rats submitted to perinatal protein undernutrition had increase in ventilation at rest and in ventilatory responses to hypercania and hypoxia, which could be a potential hidden basis for the development of arterial hypertension in adulthood.Support: FACEPE and CNPq.
Arterial Stiffness in Diet‐induced Obese Mice is Reversed by Weight Loss
Authors: Shiang Tina , Al Sayah Leona , Fry Jessica , Weisbrod Robert , Bajpai Saumendra , Reinhart‐King Cynthia , Cohen Richard , Seta Francesca 
Published: June 2021

BACKGROUNDWe previously showed that C57Bl/6J male mice fed a diet rich in fat (35%) and sucrose (16.5%) (HFHS) develop obesity, glucose intolerance, insulin resistance, chronic inflammation, cardiac diastolic and kidney dysfunctions compared to normal diet (ND). We also showed that HFHS‐fed mice develop arterial stiffness (AS), measured in vivo by pulse wave velocity (PWV), within 2 mos and systolic hypertension, measured by radiotelemetry, after 6 mos compared to ND.AIMWe sought to test the hypothesis that AS and hypertension would normalize in obese mice after reversal to ND.METHODS AND RESULTSMice fed HFHS for 5 mos were fed ND for 2.5 mos with bi‐weekly assessments of metabolic and cardiovascular parameters. Diet reversal induced a severe weight loss in obese mice with a 2‐fold reduction in fat mass and hyperinsulinemia and no change in lean mass. PWV was significantly reduced from 5.3 ± 0.7 to 3.37 ± 0.4 m/sec after 1.5 mo reversal to ND. Similarly, systolic blood pressure was significantly decreased at this time point (from 135.7 ± 3.8 to 124.2 ± 2.7 mmHg). Atomic force on aortic rings, an in vitro indicator of structural stiffness of the intima, was increased after HFHS and significantly decreased after 4 mos reversal to ND.CONCLUSIONSObesity‐induced arterial stiffness and hypertension are reversible by fat loss with normalization of metabolic state. NHLBI grant HL105287–01.
The role of the type III transforming growth factor‐β receptor Tgfbr3 in the regulation of pulmonary vascular development
Authors: Niess Gero , Wygowski Jegor , Seeger Werner , Morty Rory Edward 
Published: June 2021

Bronchopulmonary dysplasia (BPD) is associated with poor alveolar and vascular development. The molecular basis of this is not well understood. Expression studies in the lung of hyperoxia (85% O2) treated mice, a model of BPD, have revealed that the protein level of the type III TGF‐β receptor (Tgfbr3) is reduced by 4‐fold. Laser microdissection confirmed downregulated expression (mRNA level) of tgfbr3 in the pulmonary vasculature of the developing mouse lung. Immunohistochemical studies suggested that the changes in TGF‐β receptor expression were largely confined to the pulmonary vascular smooth muscle, suggesting a possible role for these receptors in the smooth muscle tissue in the development of BPD. Knockdown of TGFBR3 in primary pulmonary artery smooth muscle cells (PASMC) increased proliferation by 2‐fold, in a TGF‐β‐independent manner (observed in the presence of the TGF‐β pathway inhibitor SB431542). Migration of PASMC assessed by Boyden Assay was increased 4‐fold. However, apoptosis of PASMC was not affected by the knockdown of TGFBR3. Taken together, these data suggest a role for TGFBR3 in vascular smooth muscle cell function which could lead to a dysregulation of TGF‐β signalling in the pulmonary vasculature which in turn could contribute to the impaired pulmonary vascular growth and development associated with the lung hypoplasia observed in patients with BPD.German research foundation.
GPCR activation of CFTR through two independent phosphorylation pathways
Authors: Billet Arnaud , Hanrahan John William 
Published: June 2021

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) activation by PKA and PKC has been extensively studied, however its regulation by receptors is less well understood. To study signaling upstream of the kinases, we measured whole‐cell Cl‐currents in BHK cells cotransfected with GPCRs and CFTR. In cells expressing the M3 muscarinic acetylcholine receptor, the agonist carbachol (Cch) caused strong activation of CFTR through two pathways; the canonical PKA‐dependent mechanism and a second mechanism mechanism that involves tyrosine phosphorylation. The role of PKA was suggested by partial activation of a mutant lacking tyrosine residues that mediate stimulation by the tyrosine kinase c‐Src. The role of tyrosine kinases was suggested by the ability of Cch to stimulate 15SA CFTR, a mutant which lacks 15 potential PKA sites and is unresponsive to PKA stimulation, and also by the sensitivity of the Cch response to inhibitors of the tyrosine kinase c‐Src. The results suggest that CFTR phosphorylation by PKA and tyrosine kinases both contribute to CFTR regulation by GPCRs that are expressed at the apical membrane of intestinal and airway epithelia.Supported by GEPROM, GRASP, the McGill (CIHR) Chemical Biology program, and the Canadian Foundation for Innovation.
Sarcopenia and hypertrophy in aged skeletal muscle is independent of lifelong muscle stem cell depletion
Authors: Lee Jonah Dan , Mula Jyothi , Fry Christopher S , Kirby Tyler J , Jackson Janna R , Beggs Jake A , Campbell Marilyn S , Kmiec Tyler E , Dupont‐Versteegden Esther E , McCarthy John J , Peterson Charlotte A 
Published: June 2021

Unresolved questions in aged muscle involve whether the loss of muscle stem cells, satellite cells, contributes to sarcopenia and impedes hypertrophy of aged muscle. To directly address these questions, we developed the Pax7‐DTA mouse that conditionally and specifically ablates Pax7+ satellite cells following tamoxifen administration (TM). Four month old mice were treated with TM or vehicle and at 5 (young) or 24 (old) months of age were subjected to a synergist ablation (SA; two weeks of overload) or sham surgery. With age, vehicle treated muscles demonstrated a 52% reduction in Pax7+ satellite cells. TM treated muscles showed >;90% ablation after 1 month and no recovery after 20 months, such that the aged mice lived the majority of their lives with a significantly reduced satellite cell pool. Despite Pax7 depletion with TM, muscle mass, fiber cross‐sectional area and function were all reduced with age independent of Pax7 number. After SA, TM mice increased muscle mass and fiber cross‐sectional area to the same extent as vehicle, with old mice demonstrating an attenuated hypertrophy compared to young. Large myofiber distribution decreased with age and increased with SA, independent of Pax7 number. However, the total number of small fibers (<600 um2), relatively more abundant in aged muscle, were reduced with TM. These data provide convincing evidence the satellite cell niche does not play a role in maintenance of skeletal muscle mass across the lifespan or in hypertrophy of young or old muscle.Funding: NIH R01AR060701, R21AG34453. Ellison Foundation/American Federation of Aging Research EPD12102.
Involvement of Store‐operated cAMP signaling in the regulation of colonic secretory function
Authors: Nichols Jonathan Michael , Maiellaro Isabella , Abi‐Jaoude Joanne , Curci Silvana , Hofer Aldebaran M. 
Published: June 2021

We recently described a new mode of intracellular cAMP production that is triggered by decreases in free Ca2+ within the ER lumen and requires the luminal ER Ca2+ sensor stromal interaction molecule (STIM1). We termed this process store‐operated cAMP signaling (SOcAMPS). Here we assessed the extent to which SOcAMPS participates in epithelial Cl− transport as measured by short‐circuit current (Isc) in polarized T84 monolayers. We found that in Ca2+‐free conditions the Ca2+ionophore ionomycin and the Ca2+‐mediated agonist carbachol stimulated Cl− secretion. The effect was enhanced by the phosphodiesterase inhibitor IBMX and inhibited by the CFTR inhibitor CFTRinh‐172. The response persisted after BAPTA‐AM treatment, and was unaffected by Ba2+ (inhibits Ca2+‐activated K+ channel), or flufenamic acid (inhibits Ca2+‐activated Cl− channels). Parallel imaging measurements using FRET‐based reporters for cAMP and PKA activity showed that depletion of Ca2+ stores caused increased cAMP and PKA activation. We propose that a discrete component of the Ca2+‐ activated secretory activity in the colon derives from SOcAMPS. This alternative mode of cAMP production could contribute to the actions of diverse xenobiotic agents that disrupt ER Ca2+ homeostasis, leading to diarrhea.Support: Harvard Digestive Diseases Center, the NIDDK (1R21DK088197–01) and the Veteran's Administration (VA‐ORD 1 I01 BX000968‐01)
Evidence of donor epithelial type 2 cell engraftment in bleomycin‐injured murine lung after airway delivery
Authors: Wang Ping Ming , Martin William J 
Published: June 2021

Alveolar epithelial type 2 cells (AT2) are the alveolar progenitor cells. We hypothesized that AT2 cells obtained from normal mice could function as donor repair cells with engraftment in injured lungs with new intercellular junction expression at the alveolar level. To address this, we harvested 106AT2 cells from adult male mice, labeled the cells with DiI and airway delivered them into the lungs of female mice at day 5 following bleomycin. Lungs were isolated at day 7 or 21 after bleomycin and cryostat sectioned. We identified donor AT2 engraftment, gap and adherens junctions by immunoflourescence of DiI, connexin 43 and E‐cadherin using confocal microscopy, respectively. We found that 28 of 94 and 64 of 76 randomly selected DiI‐labeled donor AT2 cells expressed connexin 43 in the lung at day 2 and 16 following airway delivery of donor cells, respectively. The connexin 43 expression between donor and recipient cells significantly increased from 2.1 ± 1.2 (mean ± SD, n=28) per donor AT2 cell at day 2 to 7.6 ± 4.3 (n=64) at day 16 (p<0.01), suggesting that gap junction formation increased as function of time. Also, the E‐cadherin expression in DiI‐labeled donor AT2 cells increased from at day 2 to 16 following airway delivery of donor AT2 cells. These results provide evidence that airway delivered donor AT2 cell successfully engraft within alveoli of bleomycin‐injured lungs and may facilitate alveolar repair.(Funders: NICHD)
Moxonidine as an Insulin Sensitizing Agent
Authors: Edwards Lincoln Paul , Cheema Meherali , Nunemaker Craig 
Published: June 2021

Oral medications used to treat type 2 diabetes have important adverse effects. Novel agents with fewer risks are needed. Published studies indicate that moxonidine can have insulin sensitizing effects. The objective of this study is to provide insight into the mechanism(s) by which moxonidine acts as an insulin sensitizing agent. The acute and chronic effects of moxonidine on calcium handling by islet cells were determined in vitro using isolated mouse pancreatic islets. Time‐course and dose‐response studies were also carried out in cells, followed by Western blotting. Moxonidine lowered calcium levels in islet cells in a manner that was dose‐dependent up to 10nM, reversible and independent of the KATP channel. Moxonidine [1μM] caused an increased phosphorylation of both protein kinase B (PKB) and protein dependent kinase (PDK) by greater than 3 fold in HepG2 and HEK293 cells. The increased PKB phosphorylation could be blocked by efaroxan (10μM). Cells overexpressing the imidazoline receptor protein IRAS, showed greater phosphorylation of PKB compared to control, following moxonidine treatment. Moxonidine caused a time‐dependent increase in glucose uptake in HepG2 cells of up to 2.5 fold, and this could be blocked by efaroxan and by phosphatidyl inositol‐3‐ kinase inhibitor LY294002. These data suggests that moxonidine may regulate islet insulin release while sensitizing tissues to the action of insulin.These studies were supported in part by NIH1R15DK084468–01 A1and the Center for Health Disparities at Loma Linda University
Glucose metabolism and DNA methylation of offspring are altered by maternal sodium restriction
Authors: Siqueira Flavia Ramos , Nguyen PhuongSon , Kobzik Lester , de Oliveira Ivone Braga , Heimann Joel Claudio , Furukawa Luzia Naoko Shinohara 
Published: June 2021

ObjectiveTo evaluate glucose metabolism of adult offspring of dams fed low sodium diet during pregnancy.MethodsFemale Wistar rats (n= 6 – 8/group) were fed low (LS‐ 0.15%) or normal (NS‐1.3% NaCl) salt diet since the 1st day of gestation until delivery or LS during 1st (LS10) or 2 nd half of gestation (LS20). Body weight (BW), circulating glucose, insulin, leptin and C‐peptide levels, glucose (GTT) and insulin tolerance test (ITT) and leptin receptor (LR) methylation were measured in male (M) and female (F) offspring at 12 weeks of age.Results (mean±SEM, p< 0.05):BW, at birth (g, n=14 – 27/group) (M: NS = 6.5±0.1, LS = 5.5±0.1, LS10 = 6±0.1, LS20 = 4.8±0.1, F: NS = 6±0.2, LS = 5±0.1, LS10 = 6±0.1, LS20 = 4±0.1) was lower in LS, LS10 and LS20 than in NS, while at adulthood it was not different. Glucose was higher in LS (M=115±3; F=110±4) than in the other groups (M: NS=103±1; LS10=100±2; LS20=96±2; F:NS=101±2; LS10=100±2; 108±2). C‐peptide was higher in LS (M=1117±152; F=509±27) than in NS (M=375±41; F=233±63) and lower in LS20 (M=97±15; F=76±9) compared to LS10 (M=528±112; F=378±45).Glucose was higher in LS M and F at 5 minutes of the GTT compared to NS offspring. Leptin, insulin, and ITT were not different. But LR methylation was increased in LS20.ConclusionSodium restriction during pregnancy leads to low birth weight and to modifications of glucose metabolism and LR methylation. Supported by FAPESP and CAPES.
Reduction of vasoconstriction by removing periarterial nerve in human gastroepiploic artery imply prevention of vasospasm
Authors: Yokoyama yasutaka , Matsushita Satoshi , Iesaki Takafumi , Amano Atsushi 
Published: June 2021

BackgroundThe right gastroepiploic artery (GEA) is used as an in‐situ arterial graft for coronary artery bypass grafting (CABG). However, the GEA is more likely to cause vasospasms compared to the internal thoracic artery. We hypothesized that the significant cause of GEA spasms is triggered by periarterial sympathetic nerve, since the GEA is classified as a muscular artery.Materials and MethodsUnused parts of the GEA were obtained from patients who underwent CABG. The vessel was assigned to control (N+) and denervation (N−) group. For N− group, periarterial nerve was microscopically removed. These vessels were investigated by hematoxylin‐eosin (H‐E) and immunohistochemical staining. Then, each vessel was exposed to electrical field stimulation (EFS).ResultsHistological analysis revealed that the periarterial connective tissues including neuropeptide Y (NPY) were removed from lateral layer to external elastic membrane in the N−, whereas they were preserved in N+. The vasoconstriction by EFS with serial frequency was consistently lower in N− than N+ (p<0.05 at 20 and 50Hz; n=8 each). These vasoconstrictions were inhibited by tetrodotoxin. Moreover, endothelium dependent relaxation and vasoconstriction of the smooth muscle were similar in both groups.ConclusionsThe removal of periarterial nerves from human GEA can prevent graft spasms without disturbance of endothelial and smooth muscle functions.
Regulation of SERCA2a by Akt in alcoholic cardiomyopathy
Authors: Jeffress Miara Akiel , Umoh Nsini , Walker Robin , Alrubaiee Mustafa , Haddad George 
Published: June 2021

Alcoholic cardiomyopathy is one of the leading causes of non‐ischemic dilated cardiomyopathy. Approximately one in three alcoholics develops this disease. Prior studies from our lab have demonstrated the up‐regulation of intracellular calcium in dilated cardiomyopathy by Akt. SERCA2a has shown to be reduced in heart failure. Thus, we hypothesize that alcohol regulates the SERCA2a activity via the Akt pathway, affecting Ca2+ handling in cardiocytes. Thus, parallel measures of intracellular Ca2+ and sarcomere/cellular contractions were assessed (Ionoptix) with the expression level (western blot) of primary Ca2+ handling proteins (SERCA2a, phospholamban, ryanodine receptors, Na/Ca exchanger and L‐type Ca2+ channels) from control, low (LA: 0.02%), moderate (MA: 0.11%) and high (HA: 0.45%) alcoholic rat hearts with and without Ad. EGFP, Ad. Akt and Ad.Akt(K179M) transfection. Our studies indicate that SERCA2a levels are decreased in MA and HA hearts as well as those transfected with Ad.Akt. This suggests that elevated alcohol exposure induces cardiac dysfunction partly through reduction of SERCA2a activity in an Akt‐dependent manner.This work was supported in part by grants NIH/NIAAA/1R15AAA019816–01A1 and 2G12 RR003048RCMI/NCRR/NIH.
Cardio‐and cerebrovascular control in men and women with furosemide‐induced hypovolemia during artificial gravity exposure by short radius centrifuge
Authors: Zhang Qingguang , Evans Joyce M , Knapp Charles F , Falvo Michael J , Moore Fritz B , Patwardhan Abhijit R , Serrador Jorge M 
Published: June 2021

We tested cardio‐and cerebrovascular regulation in nine men and eight women during artificial gravity (AG) exposure using a short radius centrifuge while hypovolemic. ECG, beat‐by‐beat blood pressure, middle cerebral artery blood velocity (MCAv), and end‐tidal carbon dioxide (ETCO2) were measured in supine position during ~90‐min AG exposure. Dynamic cerebral autoregulation and arterial baroreflex sensitivity (BRS) were obtained with cross‐spectral analysis during 5‐min rest pre and post AG exposure, and during maximal AG. Plasma volume was reduced by 8.6% following furosemide infusion and a subsequent 5.7% with AG exposure. From pre AG rest to maximal AG, mean arterial pressure (MAP) increased, while mean MCAv, ETCO2 and BRS decreased significantly; oscillations in MAP and mean MCAv, and coherence between MAP and mean MCAv augmented significantly within the frequency range (0.07–0.20 Hz) while gain and phase remained unchanged. In post AG rest, MAP, BRS, and oscillations in MAP returned to control values, while mean MCAv and coherence between MAP and mean MCAv were significantly lower than pre AG rest. Similarly gain remained unchanged but phase was reduced significantly. We conclude that enhanced coherence suggests that autoregulation remained intact during AG exposure; MCAv and phase were reduced suggesting autoregulation may have been affected following AG.Supported by KY NASA EPSCoR Grant #NNX07AT58A, KY State Matching Grants, the NASA Johnson Space Center Human Research Program and the NASA Ames Research Center.