bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoplasmic reticulum stress contributes coronary artery dysfunction in type 2 diabetic mice (1086.7)
Authors: Choi Soo‐Kyoung , Lee Young‐Ho 
Published: June 2021

Background: Vascular dysfunction is a major complication in type 2 diabetes. Although endoplasmic reticulum (ER) stress has been suggested to be a contributing factor in cardiovascular diseases, the relationship between ER stress and type 2 diabetic vascular dysfunction remains unclear. Thus, in the present study, we examined whether ER stress contributes coronary artery dysfunction and ER stress inhibition ameliorates vascular function in type 2 diabetes. Methods and Results: Type 2 diabetic and their control mice were treated with or without ER stress inhibitors (taurine‐conjugated ursodeoxycholic acid, TUDCA, and 4‐phenylbutyric acid, 4‐PBA) for 2 weeks. In type 2 diabetic mice, blood glucose, body weight, and insulin level are elevated compared to control mice. The myogenic response is potentiated and endothelium‐dependent relaxation is impaired in type 2 diabetic mice. Interestingly, treatment of ER stress inhibitors normalized myogenic responses and endothelium dependent relaxation.These data were associated with an increase in ER stress marker expression (CHOP, ATF6, XBP‐1, and phosphorylated‐eIF2α) in heart and mesenteric resistance arteries in type 2 diabetic mice, which were reduced by treatment with ER stress inhibitors. Conclusion: ER stress inhibition normalizes myogenic response and improves vascular function in type 2 diabetes. Therefore, ER stress could be a potential target for cardiovascular diseases in diabetes mellitus.Grant Funding Source: supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF)
Prenatal taurine supplementation decreases adult renal function by mechanisms other than taurine inhibition of prenatal renin‐angiotensin system (1087.1)
Authors: Roysommuti Sanya , Kritsongsakchai Angkana , Wyss J. 
Published: June 2021

Taurine inhibits renin‐angiotensin system (RAS). This study tests the hypothesis that the effect of perinatal taurine supplementation on adult renal function is primarily due to prenatal inhibition of the RAS by taurine. Female Sprague‐Dawley rats were fed normal rat chow and given water alone (control) or water containing captopril (400 mg/ml; captopril) or 3% taurine (taurine) from conception until delivery. Then, the rats received normal rat chow and tap water. At 7‐8 weeks of age, renal function at rest and after acute saline load (5% of body weight) was studied in conscious, restrained male rats. Compared to control, prenatal taurine but not captopril treatment slightly increased mean arterial pressure but not heart rate in adult rats. In taurine compared to control and captopril groups, renal blood flow significantly decreased whereas renal vascular resistance significantly increased. Glomerular filtration, filtration fraction, diuretic and natriuretic responses to acute saline load were significantly increased in captopril compared to the other two groups. These data indicate that the prenatal inhibition of RAS increases renal glomerular and tubular functions, while the prenatal taurine supplementation worsens renal vascular and blood pressure control. Thus, the effect of perinatal taurine supplementation on adult renal function is not related to the ability of prenatal taurine to inhibit the RAS.Grant Funding Source: Supported by Khon Kaen University
Expression of an angiotensin‐(1‐7) endopeptidase in proximal tubules of the sheep and human kidney (1088.10)
Authors: Wilson Bryan , Marshall Allyson , Pirro Nancy , Su Yixin , Rose James , Chappell Mark 
Published: June 2021

Angiotensin‐(1‐7) [Ang 7] is a an active peptide of the renin‐angiotensin system (RAS) that generally antagonizes the actions of Ang II. Within the kidney, Ang 7 is derived from Ang I by endopeptidases including neprilysin (NEP) and thimet oligopeptidase (TOP) or from Ang II by the carboxypeptidase ACE2. Ang 7 is primarily degraded by ACE to the Ang‐(1‐5) in the circulation and tissues; however, we identified an endopeptidase in sheep CSF that efficiently degraded Ang 7 to Ang‐(1‐4) (Ang 4) and accounted for the majority of Ang 7 metabolism in this compartment (Marshall et al AJP 2013). The current study determined whether the Ang 7 peptidase is expressed in the kidney, specifically in isolated proximal tubules of the sheep and human renal epithelial cells. Activity was determined by the conversion of 125I‐Ang 7 to 125I‐Ang 4 in a 100,000 xg supernatant fraction. Both the sheep proximal tubules and the human epithelial cells expressed Ang 7 endopeptidase activity. Kinetic analysis revealed an apparent Km of 2.0 ± 1.0 µM and apparent Vmax’ of 93 ± 37 pmol/min/mg protein [n=3]. Peptidase activity in the isolated tubules was attenuated by the metalloendopeptidase inhibitor JMV‐390 with an IC50 of 0.81 ± 0.12 nM [n=3] that is ~50‐fold more potent than that of NEP and TOP. We conclude that an Ang 7 endopeptidase may be a novel component of the intrarenal RAS to regulate the tubular expression of Ang 7.Grant Funding Source: Supported by NIH grants HL56973, HL52972, HL112237, and HD047584
Adaptation of chronic renal microdialysis to evaluate the role of interstitial ATP and angiotensin II in accelerating nephropathy and oxidative stress during insulin induced hypertension (1088.3)
Authors: Prathipati Priyanka , Alanazi Wael , Fakhruddin Fnu , Jackson Debra , Jackson Keith 
Published: June 2021

Various studies demonstrated the role of ATP in regulating hemodynamic functions and play a key role in maintaining tubuloglomerularfeedback (TGF) and renal vascular resistance. Previous studies also demonstrated the role of Ang II and HO‐1 in regulating blood pressure. We thus hypothesize that insulin induced hypoglycemia augments interstitial ATP levels which in turn increases AngII. This stimulates afferent arteriolar vasoconstriction interrupting normal TGF mechanism resulting in hypertension leading to oxidative stress and ultimately renal damage. Male Sprague Dawley rats (200‐225g) were anesthetized and microdialysis probe was inserted into their renal cortex. Post surgery rats were treated with insulin (7U/kg body weight) or vehicle for 2 weeks. Dialysate was collected daily after insulin dosing and analyzed for ATP by luciferin‐luciferase assay and Ang II by ELISA. ATP levels were elevated from 4.75 ng (day 0) to 36.47 ng (day 14). Heart and kidneys were collected at the end and analyzed for oxidative stress using EPR (Electron Paramagnetic Resonance). Oxidative stress was observed from the spectra obtained by using spin probes CMH and CPH. Thus the present study demonstrates a correlation between interstitial ATP and oxidative stress by real‐time chronic collection of renal interstitial samples, demonstrating the ability of hypoglycemia to promote the development of hypertension in turn accelerating oxidative stress.Grant Funding Source: Board of Regents Research Competitiveness 2010
Glucagon‐like peptide 1 receptor activation acutely increases systolic blood pressure independent of aldosterone‐mediated sodium retention (1088.8)
Authors: Moreno Meagan , Rodriguez Ruben , Lee Andrew , Vazquez Guillermo , Ruilova Steven , Ortiz Rudy 
Published: June 2021

Metabolic syndrome is associated with increased activation of the renin‐angiotensin system, high blood pressure and decreased circulating levels of glucagon‐like peptide‐1 (GLP‐1). GLP‐1 mimetics have been shown to decrease systolic blood pressure (SBP) via unknown mechanisms. To assess the effects of angiotensin receptor type 1 (AT1) and GLP‐1 receptor (GLP‐1r) activation on SBP, urinary Na+ (UNaV), aldosterone (UAldoV), and corticosterone (UBV) excretion were recorded for six weeks in five groups of rats: 1) untreated, lean LETO (n=7), 2) untreated, obese OLETF (n=5), 3) OLETF + AT1 blocker (ARB; 10 mg olmesartan /kg/d; n=4), 4) OLETF + GLP‐1 mimetic (Ex; 10 ug exenatide/kg/d; n=7), and 5) OLETF + ARB + Ex (combo; n=6). Ex UAldoV and UBV increased 207% and 123%, respectively, compared to OLETF on day 2 and were associated with a 62% UNaV decrease and 8% SBP increase. However, the 13% reduction in UAldoV in combo was associated with 94% increase in UBV, and 80% and 16% decrease in UNaV and SBP, respectively, compared to OLETF suggesting that activation of AT1 has a greater contribution to the insulin resistance‐associated increase in SBP than impaired UNaV. By day 7, Ex UAldoV was 48% lower than OLETF, but UBV, UNaV, and SBP were similar to OLETF. While GLP‐1r activation acutely increases SBP independently of aldosterone‐mediated sodium retention, ultimately the effect is rectified SBP and normalization of UNaV.Grant Funding Source: Amylin Pharmaceuticals (Bristol‐Myers Squibb)
microRNA‐301b reduces PPARγ expression in transgenic sickle mice and in hemin‐treated human pulmonary artery endothelial cells (1089.22)
Authors: Kang Bum‐Yong , Tan Fang , Samit Ghosh , Archer David , Sutliff Roy , Ofori‐Acquah Solomon , Hart C. Michael 
Published: June 2021

Sickle cell disease (SCD) is characterized by chronic intravascular hemolysis resulting in the release of hemin into the blood. Our preliminary microarray data indicate that PPARγ expression is significantly reduced in hemin‐treated human pulmonary artery endothelial cells (HPAECs). To examine post‐transcriptional mechanisms of PPARγ regulation in pulmonary hypertension in SCD (SCD‐PH), Townes knockin SCD mice aged 12‐weeks were gavaged daily with vehicle or rosiglitazone (RSG, 10 mg/kg/day) for 10 d. PPARγ was decreased and ET‐1 expression was increased in sickle mice (SS) compared to littermate control mice (AA). Using an in vitro model that mimics acute extracellular hemin release, HPAECs were treated with DMSO or hemin (5 μM) for 72 h ± RSG (10 μM) for the final 24 h. Similarly, hemin reduced PPARγ and increased ET‐1 expression in HPAECs. MicroRNA (miR‐301b), which negatively regulates PPARγ, was increased in SCD mice and in hemin‐treated HPAECs. In contrast, PPARγ activation attenuates increases in miR‐301b levels in SS mice and in hemin‐induced HPAECs. These findings suggest that hemolysis in SCD increases miR‐301b to reduce PPARγ and increase ET‐1 levels. These results suggest novel pathways for SCD‐PH pathogenesis and therapy.Grant Funding Source: Supported by AHA‐SDG 13SDG14150004,CEB F16788‐00, Atlanta VA 1I01BX001910, NIH HL074518, DK102167
Antenatal chronic hypoxia and L‐type Ca2+‐dependent contractility of pulmonary arteries from fetal sheep (1089.6)
Authors: Brunelle Alex , Blood Quintin , Longo Lawrence , Wilson Sean 
Published: June 2021

Recently we and others have shown that K+‐depolarization induced pulmonary arterial (PA) contraction is due to the combined activation of L‐type Ca2+ channels (CaL) and Rho kinase (ROK). In fetal sheep we demonstrated that CaL inhibition with nifedipine (NIF) reduced 125 mM K+‐mediated contraction up to about one‐half, with ROK contributing the remainder, and that the relationship between these two pathways was preserved following antenatal chronic hypoxia (CH). To better define the relationship between these pathways and the impact of antenatal CH, we tested the hypothesis that direct activation of CaL would elicit a NIF sensitive contraction and this contraction would be preserved following antenatal CH. This was examined using wire‐myography approaches on small diameter PA isolated from normoxic (~700 m) and antenatal CH (3,801 m, for >100 days) late gestation fetal sheep. Our results show that direct activation of CaL with 10 μM FPL 64176 (FPL) elicited a contraction that was approximately 80‐125% of the maximum K+‐induced depolarization (TKmax) in normoxic and hypoxic PA. In both normoxic and hypoxic PA 10 μM NIF reduced FPL‐induced contraction back to baseline. These data illustrate that NIF‐sensitive CaL‐dependent contraction is preserved following antenatal CH and when compared to our previous work that direct CaL activation causes fetal PA constriction in a distinct way compared to K+‐depolarization.Grant Funding Source: Supported by NSF MRI 0923559, NIH HD‐069746, P01HD031226, R01HD003807
Mutant BMPR2 expression in cardiomyocytes results in an altered hypertrophic response (1090.2)
Authors: Talati Megha , Funke Mitchell , Bylund Jeffery , Trammell Aaron , Majka Susan , Fessel Joshua , West James , Newman John , Hatzopoulos Antonis , Hemnes Anna 
Published: June 2021

Background: End‐stage pulmonary arterial hypertension (PAH) is characterized by right ventricular (RV) dysfunction, failure and death. We have shown BMPR2 mutation is associated with impaired RV hypertrophy and cardiomyocyte lipid deposition in both heritable PAH patients and a murine model of mutant BMPR2 expression.Hypothesis: BMPR2 mutation alters hypertrophic response and fatty acid transport in RV cardiomyocytes.Methods: Stable mouse embryonic stem cell lines (ESC) were engineered to express BMPR2 mutation using pCI‐Neo‐BMPR2 plasmids with mutation in either cytoplasmic (CD) or kinase domain (KD) or a linearized pCI‐Neo vector (Control) and gene expression confirmed by RT‐PCR. Directed differentiation of the ESC to cardiac myocytes (ESC CM) performed using noggin. ESC CM treated with phenylephrine for 72 hours to induce hypertrophy. Western analysis performed for proteins: CD36 (a fatty acid transporter molecule), brain natriuretic peptide (BNP) and corin (a serine peptidase which cleaves pro‐BNP). Oil‐red‐O stain performed for intracellular lipid deposition in ESC‐CM.Results: All ESC‐CM expressed α‐SMA and demonstrated characteristic contraction in vitro. In response to hypertrophy, control ESC CM increased expression of BNP and corin, which remained unchanged in CD and KD BMPR2 mutant cells.At baseline expression of CD36 protein was higher in CD BMPR2 mutant containing ESC CM and Oil‐red‐O staining suggested increased intracellular lipid accumulation in mutant ESC CM relative to control cells. Hypertrophic stimulus reduced the expression of CD36 in CD and KD BMPR2 ESC CM compared to control cells.Conclusions: Altered BMPR2 signaling due to CD or KD mutations in ESC CM were associated with an impaired hypertrophic response. This impaired response was associated with decreased expression of BNP, corin and CD36. This may explain reduced ability of RV to adapt to increased RV afterload in PAH. Further characterization of the mechanism of impaired hypertrophy is planned.Grant Funding Source: P01HL108800
KCC and NKCC activity affect spike frequency adaptation in CO2‐sensitive avian intrapulmonary chemoreceptors (1092.3)
Authors: Meehan Shane , Bassett Peter , Lonjaret Jean‐Guillaume , Hempleman Steve , Sheridan Krystal 
Published: June 2021

IPC are respiratory chemoreceptors that exhibit SFA, have phasic and tonic CO2 sensitivity, and help control breathing in birds. In IPC, large changes in PCO2, pHi, and [HCO3]i occur with each breath. Here we test the hypothesis that Cl‐ transmembrane flux may be involved in IPC CO2 transduction to balance intracellular [HCO3‐] changes. Furosemide (FU), an equipotent inhibitor of both K+ ‐Cl‐ cotransport (KCC), which allows for Cl‐ efflux driven by the K+ gradient, and Na+ ‐K+ ‐2Cl‐ cotransport (NKCC), which allows for Cl‐ influx driven by the Na+ gradient, was given to anesthetized Anas platyrhynchos (N=6) while recording single‐unit IPC. FU progressively reduced SFA at 10‐40 mg/kg (p蠄0.0001). In contrast, tonic IPC discharge was decreased at low FU doses (0.5‐5 mg/kg, p蠄0.0001) but increased at higher dosages (10‐40 mg/kg, p蠄0.0001). Results suggest that IPC SFA and tonic CO2 sensitivity are influenced by KCC and/or NKCC, presumably by reducing ability of the cell to produce Cl‐ counter movements required by phasic [HCO3‐] changes.Grant Funding Source: Supported by NIH R15 HL087269‐02
CORM‐3 derived CO suppresses NLRP3 inflammasome in cardiac fibroblasts and protects cardiomyocytes from apoptosis in mice with sepsis (1096.6)
Authors: Zhang Wenbo , Xu Xuemei , Mele Tina , Kao Raymond , Cepinskas Gediminas , Martin Claudio , Rui Tao 
Published: June 2021

The study is to examine the role of CO derived from CORM‐3 on NLRP3 inflammasome activation in cardiac fibroblast (CF) and its effect on cardiomyocyte apoptosis and myocardial dysfunction in mice with sepsis. Methods: CFs were primed with LPS and followed by ATP treatment with or without CORM‐3. CF NLRP3 expression and NLRP3 inflammasome activation assessed. Cardiomyocyte apoptosis and myocardial function were measured in mice with LPS. Results: LPS priming and ATP treatment to CFs resulted in NLRP3 inflammasome activation as indicated by increase in cleaved caspase‐1 p20 and matured IL‐1β. CFs with NLRP3 siRNA abolished caspase‐1 cleavage and IL‐1β maturation. CORM‐3 attenuated the increase in NLRP3 and pro‐IL‐1β expression in LPS primed CFs and prevented NLRP3 inflammasome activation. CORM‐3 inhibited NLRP3‐mediated ASC pyroptosome formation. Myocardial NLRP3, pro‐capase‐1, p20, pro‐IL‐1β and IL‐1β were increased, cardiomyocyte apoptosis was induced and myocardial contractility was decreased in mice with LPS. CORM3 prevented the myocardial NLPR3 inflammasome activation, attenuated cardiomyocytes apoptosis, and improved cardiac function in mice with LPS. Conclusions: CORM‐3‐derived CO suppresses NLRP3 inflammasome priming and activation in CFs and protects myocardium from apoptosis and dysfunction in mice with endotoxemia. (HSFO 2012‐000212)Grant Funding Source: Heart and Stroke Foundation of Ontario
The effects of hypersalinity on the physiology and morphology of a livebearing fish (1100.12)
Authors: Castellanos Krystal , Cavazos Corrina , Weaver Kathleen , Garcia Jerome , Weaver Pablo 
Published: June 2021

The Poeciliidae family of livebearing fish exhibit broad environmental tolerances and occupy some of the most extreme aquatic environments on earth. One group in particular, the Limia genus, is widespread throughout freshwater habitats in the Dominican Republic and has also colonized hypersaline lagoons at salinity levels more than twice that of sea water. Populations found in hypersaline conditions appear to be smaller and less colorful than their freshwater counterparts. We hypothesize that these changes to morphology may be related to the energetic cost of osmoregulation in an extremely hypertonic environment. Here we use geometric morphometrics to quantify morphological differences, including size and shape, of freshwater and hypersaline populations of L. perugiae. We correlate changes to size and shape with an increase in energy usage by the active ion transport mechanisms of the mitochondria rich cells in the gill tissues.Grant Funding Source: Supported by Title V STEM, Rose Hills, University of La Verne Faculty Research Grant
Influence of myostatin on skeletal muscle plasticity (1102.22)
Authors: Reisz‐Porszasz Suzanne , Abraham Andrea , Baker Michael , Caiozzo Vincent 
Published: June 2021

Goal: to investigate the role of myostatin (Mst) in adult skeletal muscle structure, function and physical performance. We generated the conditional Mst overexpressing transgenic (CMOT) mice in which Mst expression can be switched ON or OFF. Methods: We used mechanical overloading (MO) (bilateral synergist ablation of plantaris muscle) to determine the role of Mst in muscle structure and function in Mst KO (knockout), TG (transgenic), CMOT and WT (wild type) animals. Results: In CMOT mice, Mst level was 5 ‐10 times higher compared to WT followed by doxycyclin treatment. After 6 weeks of MO surgery, plantaris muscle specific tension was the highest, but not significant in CMOT; muscle mass increased in each groups, the biggest increase (200%) was in Mst TG; total cross sectional area and fiber number had increased with the highest rate (2.3x and 1,4x, respectively) in CMOT. Succinate dehydrogenase (SDH) was determined, SDH positive fiber number significantly increased in Mst KO and CMOT; the oxidative fiber ratio was the highest (45.3%), while the SHD negative fiber ration was the lowest (21.6%) in CMOT mice. In CMOT animals, TGF‐beta, insulin, Wnt, LDL, PI3K/Akt and p53 signaling pathways were up‐regulated. Conclusion: We have established an animal model, the CMOT with which we can investigate the correlation between Mst levels and muscle wasting in adulthood and the possible therapeutic intervention of muscle loss.Grant Funding Source: NIH/NIAMSD R21AR054101
Motor unit recruitment patterns in genioglossus and first dorsal interosseous (1102.4)
Authors: Shumway Karlie , Porfirio David , Bailey Fiona 
Published: June 2021

The nervous system regulates force via two means; rate coding and recruitment. In a previous study (Bailey et al. 2007) we reported on rate coding of genioglossus (GG) motor units (MUs) in the context of voluntary tongue movement. Here we focus on MU recruitment and compare GG with first dorsal interosseous (FDI). We recorded single MU action potentials via intramuscular tungsten microelectrodes inserted into the GG and FDI in 9 healthy adults (N=3 men; N=6 women). Recruitment was elicited in FDI via force increments associated with finger abduction (force range 4‐7% of max), while recruitment in the GG was elicited via increments in sound pressure level (loudness range 5‐34% of max) associated with articulation of the vowel /i/. We noted significantly higher firing rates in GG MUs at recruitment relative to FDI (18.9 4.8 vs. 11.0 2.8). Once recruited, GG MUs discharged at significantly higher rates than FDI MUs (20.9 4.7 vs. 12.1 2.7). Moreover, the firing rates of subsequently recruited units was also notably higher for GG than for FDI (21.3 4.8 vs. 12.2 2.7). These findings provide useful insights into motoneuron pools that regulate movements of the tongue in speech and of the hand in grasping. Higher firing rates at recruitment for GG compared to FDI, given comparable pressure/force ranges, suggest hypoglossal motoneurons have a shorter duration after hyperpolarization than spinal motoneurons (Bailey et al. 2007).Grant Funding Source: Supported by the National Institute of Health Grant (DC 009587)