bluuebunny/crossref_metadata_2025_split huggingface dataset:
An increase in prefrontal oxygenation at the start of voluntary cycling exercise was observed independently of exercise effort and muscle mass
Authors: Asahara Ryota , Endo Kana , Liang Nan , Matsukawa Kanji 
Published: June 2021

We have reported using near‐infrared spectroscopy that an increase in prefrontal oxygenated‐hemoglobin concentration (Oxy‐Hb) at the start of cycling exercise has relation to central command, defined as a feedforward signal descending from higher brain centers. The final output of central command evokes the cardiovascular responses depending on exercise effort. If the prefrontal cortex may output the final signal of central command toward the autonomic nervous system, the prefrontal oxygenation should increase depending on exercise effort. To test the hypothesis, we investigated the effects of exercise intensity and muscle mass on prefrontal oxygenation by longitudinal comparisons in 13 subjects. The subjects performed one‐ or two‐legged cycling at various relative intensities (20%, 35%, 45%, and 60% of maximal voluntary exercise intensity) for 1 min. The prefrontal Oxy‐Hb and cardiovascular variables were simultaneously measured during exercise. The increase in cardiac output and the decrease in total peripheral resistance at the start of one‐ and two‐legged cycling were augmented (P<0.05) in proportion to exercise intensity and/or muscle mass recruitment. However, the increase in prefrontal Oxy‐Hb seemed independent of exercise intensity. When the rating of perceived exertion was equal, the increase in prefrontal Oxy‐Hb was not different (P>0.05) between one‐and two‐legged cycling. Furthermore, no correlations (P>0.05) were found between the increase in prefrontal Oxy‐Hb and exercise intensity or rating of perceived exertion. It is likely that increased prefrontal oxygenation at the start of cycling exercise does not represent the final output of central command descending to the autonomic nervous system.Support or Funding InformationThis study was funded by Grant‐in‐Aid (15H03061) for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Aquaporin 1 regulates pulmonary arterial smooth muscle cell apoptosis
Authors: Yun Xin , Jiang Haiyang , Huetsch John , Damarla Mahendra , Shimoda Larissa 
Published: June 2021

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by functional and structural vascular changes that lead to right heart failure and death. PAH pathogenesis involves remodeling of distal small diameter pulmonary arteries, including the development of vaso‐occlusive lesions featuring proliferation, migration and reduced apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Patients often present with late disease, where targeting apoptosis to reverse remodeling would be of benefit; unfortunately, no such therapy currently exists. Apoptosis is a complex process, often involving disruption of the mitochondrial membrane and release of cytochrome c to activate the downstream effector, caspase 3, the final executioner of apoptosis. Formerly, we showed that the water channel protein, aquaporin 1 (AQP1), is a key molecule mediating PASMC proliferation and migration by increasing β‐catenin levels. Others have shown in different cell types that activating β‐catenin prevent apoptosis and improved cell survival. Therefore, in this study, we explored whether AQP1 also regulates PASMC survival and/or susceptibility to apoptosis. Primary cultured rat distal PASMCs were isolated from the SU5416‐hypoxia (SuHx) rat model of PAH or control rats. PASMCs from SuHx rats exhibited lack of apoptosis, measured by: 1) visualizing nuclear morphology via Hoechst 33342 staining; 2) cleaved caspase 3 expressions; and 3) caspase 3 activity, both at baseline and in response to the apoptotic stimuli staurosporine (ST) or H2O2. AQP1 mRNA and protein expression were significantly elevated in PASMCs from SuHx rats. Not surprisingly, β‐catenin levels were also elevated in these cells. Compared to non‐targeting siRNA, depleting AQP1 induced apoptosis at baseline in both control and SuHx rat PASMCs. Furthermore, reduction of AQP1 sensitized SuHx PASMCs to apoptotic stimuli. Our results indicate that AQP1 is a critical regulator of apoptosis in PASMCs, controlling caspase 3 activation, potentially through a pathway involving β‐catenin. Moreover, these findings suggest the possibility that targeting AQP1 might provide an attractive therapeutic option to both stop the progression of, and even reverse, vascular remodeling in PAH.Support or Funding InformationHL126514This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exposure to Leukotriene E4 Induces Hypersensitivity of Vagal Pulmonary Sensory Neurons in Rats
Authors: Gu Qihai (David) , Emamifar Nick , Gilbert Carolyn , McLaurin Hugh 
Published: June 2021

Leukotrienes E4 (LTE4), the most stable and abundant cysteinyl leukotrienes (CysLTs), has been generally studied less than other two CysLTs (LTC4 and LTD4), likely because it is only a weak agonist for the classical type 1 (CysLT1) and type 2 (CysLT2) receptors for CysLTs. However, recent identification of GRP99 protein as a high affinity receptor for LTE4 suggests that LTE4 may play a more pivotal role in the pathogenesis of airway inflammatory diseases such as asthma. The present study is carried out to investigate the effect of LTE4 on the chemo‐sensitivity of pulmonary afferent neurons in both whole‐animal ventilatory and single neuron electrophysiological recordings. In anesthetized spontaneously breathing rats, intratracheal instillation of LTE4 (2 nmol in 100 μl saline) significantly potentiates chemoreflexes evoked by right‐atrial injection of capsaicin, a specific agonist for transient receptor potential vanilloid receptor 1 (TRPV1). In patch‐clamp recordings with isolated rat vagal pulmonary sensory neurons, pretreatment with LTE4 concentration‐dependently enhances capsaicin‐induced TRPV1‐mediated whole‐cell inward currents. Our patch‐clamp experiments further demonstrate that the zinc‐evoked TRPA1‐mediated current is also markedly enhanced in these neurons. In summary, our data show that exposure to LTE4 leads to hypersensitivity of vagal pulmonary sensory neurons and augments pulmonary chemoreflexes in rats.Support or Funding InformationSupported by MUSM and Navicent Health FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Constitutive Model of Ovine Left and Right Ventricles Biaxial Mechanical Properties
Authors: Liu Wenqiang , Labus Kevin M. , Nguyen‐Truong Michael , McGilvray Kirk , Puttlitz Christian M. , Wang Zhijie 
Published: June 2021

Ventricular dysfunction is the most common cause of heart failure, which contributes significantly to mortality and morbidity in the modern society. To better understand the mechanism of the left‐ and right‐ventricle (LV and RV) failure, especially cardiac diastolic dysfunction, it is important to investigate the myocardial biaxial mechanical properties. Prior research has been focused on LV alone and has been limited to small animal models. Hence, there is a lack of study on the RV including the fundamental mechanical differences between LV and RV. Furthermore, there is a lack of data on the mechanical properties in large animal hearts (e.g., sheep) which better mimics the human heart. Our goal here was to characterize the biaxial mechanical properties of healthy sheep LV and RV tissue through constitutive modeling. In this study, a constitutive model (modified Ogden model) that is commonly used for the anisotropic hyperelastic tissue's analysis was applied to capture the biaxial mechanical behavior of the heart obtained by ex vivo experiments. The biaxial mechanical behavior was distinct between the RV and LV in both circumferential and longitudinal directions. We found that the model fit the experimental curve better for RV than LV (Figure). Furthermore, the LV and RV had different model parameters including infinitesimal shear modulus μ, nonlinearity α and anisotropy k (Table). Our results indicated that overall, the RV is stiffer in the longitudinal direction than the circumferential direction (positive k), whereas the LV is stiffer in the circumferential direction (negative k). The RV exhibited a greater degree of anisotropy than the LV, based on the magnitude of the k parameter. The RV has slightly more linear behavior (a smaller α) than the LV (a larger α). To date, this is the first study to investigate and compare biaxial mechanical behavior between LV and RV in sheep using a constitutive modeling approach. The study of the cardiac mechanics will deepen the understanding of physiological and pathological mechanisms of the myocardium. Future work will involve developing a better model for LV biaxial behavior and include more structure parameters such as collagen fiber orientation and distribution.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Characterizing Exogenous Cell Engraftment for Cystic Fibrosis Cell Therapy
Authors: Lee Rhianna Elizabeth , Miller Sean Michael , Mascenik Teresa Mary , Tarran Robert , Randell Scott Howard 
Published: June 2021

Cell therapy is a potential method for treating cystic fibrosis (CF), although cell engraftment into the highly resistive, pseudostratified human bronchial epithelium (HBE) is a major challenge. Transient epithelial injury is an approach to improve cell uptake, but the extent of injury required and the ability of cells grown by alternative methods to engraft are poorly understood. Our overarching hypothesis is that compounds such as polidocanol, an FDA approved drug used to sclerose varicose veins, can increase cell engraftment by targeting luminal barrier cells. To test this hypothesis, we engrafted exogenous, adenovirus‐EGFP transduced primary human airway epithelial cells into well‐differentiated air‐liquid interface (ALI) HBE cell cultures following treatment with varying doses of polidocanol. Quantitation of cell engraftment demonstrated that 0.125% polidocanol increased engraftment without causing overall ALI cell culture lysis. Further confocal microscopy characterization of the polidocanol injury indicates that engraftment does not require epithelial denudation to the level of the basal lamina. Primary HBE ALI cultures were then injured with polidocanol and the recovery of transepithelial electrical resistance was tracked over time after addition of no cells, conventionally‐grown cells, or cells grown with the conditionally reprogrammed cell (CRC) method. Cell engraftment expedites epithelial restoration, and CRC‐grown cells encourage recovery sooner than conventionally‐grown cells. CF ALI HBE cell cultures engrafted with non‐CF cells were tested for functional CFTR recovery in Ussing chambers. CRC HBE cells engraft, persist and recapitulate CFTR function more effectively than conventionally‐grown cells. Our results suggest that transient polidocanol injury and the CRC culture method may be a viable approach to enhance cell engraftment for CF cell therapy.Support or Funding InformationSupported by CFF grants RANDELXX015 and BOUCHE15R0CF2015, and NIH grants U01HL111018 and P30DK065988.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increased global lysine acetylation in diabetic vasculature is associated with downregulation of SIRT‐1 in vascular smooth muscle cells.
Authors: Johnson Christina Mary , Burke Cameron , Carrillo‐Sepulveda Maria Alicia 
Published: June 2021

Vascular complications are the main problems faced by patients with Type 2 Diabetes Mellitus (T2DM). In addition to endothelial dysfunction, vascular smooth muscle cell (VSMC) dysfunction is postulated to play a crucial role in the development of diabetic vascular complications. Recent studies from our laboratory have demonstrated that acetylation of lysine residues, a posttranslational modification, is increased in vascular tissue exposed to metabolic disorders, such as diabetes. We hypothesized that diabetic conditions would dysregulate lysine deacetylases and acetyltransferases in VSMC, consequently leading to increased global lysine acetylation in diabetic blood vessels. Using male adult Goto‐Kakizaki (GK) rats (16‐weeks‐old) as a model of non‐obese type 2 diabetes and their respective Wistar controls, we found that these diabetic rats exhibited high levels of fasting blood glucose (191 ± 12 vs. 98±7 mg/dL vs. controls, p<0.05), as well as hemoglobin A1C (6.82 ± 0.93 vs. 5.2 ±0.2 % controls, p<0.01). Through direct measurement of blood pressure via right carotid catheterization, we also found greater systolic blood pressure in the GK group (166.57 ±24.27 vs. 124.58 ±17.07 controls, p<0.01). This effect was accompanied by high levels of global lysine acetylation in GK blood vessels (3.3 fold of increase vs. control, p<0.001). To test our hypothesis that VSMC is a major cell type in blood vessels contributing to increased vascular lysine acetylation in diabetic conditions, we utilized isolated aortic VSMC from GK rats in primary cultures. After euthanasia with isoflurane (via nasal 5% in 100% O2), thoracic aortas from GK rats were dissected and VSMC were isolated by an enzymatic digestion method. Phenotypically, VSMC from GK rats exhibited an enhanced proliferative phenotype in comparison to VSMC from Wistar control rats (Figure 1). Strikingly, we found that VSMC from GK rats exhibited a marked decrease in SIRT‐1 deacetylase expression (3.5‐fold decrease vs. control, p<0.05). Moreover, expression of the acetyltransferase PCAF was increased in VSMC from GK rats (1.5‐fold increase vs. control, p<0.05). Taken together, our in vitro results suggest that downregulation of SIRT‐1 and upregulation of PCAF may mediate the increased levels of global lysine acetylation in diabetic blood vessels, confirming our hypothesis. To further this investigation, we will identify the proteins that are specifically acetylated in diabetic VSMC through mass spectrometry analysis, as well as the effects on global lysine acetylation when overexpressing SIRT‐1 in VSMC.Support or Funding InformationIn‐House Grant, NYITThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Resuscitation with Anaerobically Stored Blood
Authors: Williams Alexander Thomas , Yoshida Tatsuro , Dunham Andrew , Cabrales Pedro 
Published: June 2021

BackgroundHemorrhagic shock (HS) severely decreases oxygen (O2) delivery and induces cardiovascular collapse. In parallel to controlling the hemorrhage, doctors respond by infusing large volumes of red blood cells (RBCs) to restore blood volume, O2 carrying capacity, and hemodynamic stability. The quality of the transfused RBCs determines the recovery from HS, and extent of sequelae prompted by the HS. This study compares the ability to recover from HS with conventionally stored RBCs, anaerobically (O2 saturation <10%) stored RBCs, and anaerobic/hypercapnic (O2 saturation <10% & pCO2 (@37°C) ~70 mmHg) stored RBCs.MethodsPacked red blood cells (pRBCs) stored in AS‐3 after leukorfiltration were created from donor rats. pRBC were randomly stored under 1) conventional; 2) anaerobic; 3) anaerobic/hypercapnic conditions. Sprague‐Dawley rats (150–200g) were hemorrhaged (50% of blood volume), held in hypovolemia for 30 minutes, and resuscitated to recover blood pressure to 90% pre‐hemorrhage with pRBC stored for 3 weeks. Systemic hemodynamics, cardiac function, and blood gas parameters were monitored during shock and resuscitation. Vital organ inflammation, oxygenation, and function were evaluated post resuscitation. Data were analyzed using two‐way ANOVA, followed by the appropriate post hoc analyses.ResultsConventionally stored RBCs were susceptible to both biochemical and mechanical changes during storage compared to anaerobic and anaerobic/hypercapnic storage. 24‐hour post transfusion recovery of anaerobically and anaerobic/hypercapnic stored RBCs was significantly higher compared to conventionally stored RBCs (P<0.05). Shock impaired cardiac function and oxygen delivery and resuscitation with pRBCs restored cardiac output. Resuscitation with conventionally stored cells resulted in severe cardiac ischemia. Resuscitation with either anaerobic or anaerobic/hypercapnic required significantly lower volume (1.9 and 2 fewer units than conventional storage) of pRBC to preserve hemodynamics during resuscitation (P < 0.05). Animals resuscitated with conventionally stored RBCs showed impaired ability to deliver O2 to tissues, increased lung, liver, and spleen inflammatory markers, and decreased liver and kidney function, compared to animals resuscitated with either anaerobic or anaerobic/hypercapnic pRBC.ConclusionStudies indicate that anaerobic or anaerobic/hypercapnic storage of RBC can improve clinical outcomes from hemorrhagic shock in a rat model, as evidenced by hemodynamic stability, O2 delivery, and vital organ inflammation and function.Support or Funding InformationNIH Grants from the National Heart Lung and Blood Institute, T32‐HL105373, P01‐HL110900, R01‐HL126945. Financial support was received for Hemanext for the completion of the study. Hemanext did not participate in the implementation of the study.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vascular Localization of Zika Virus Following in vivo Infection
Authors: Brown Isola A.M. , DeLalio Leon J. , Liu Shufeng , Isakson Brant E. , Wang Tony T. 
Published: June 2021

Zika virus (ZIKV) is an emerging blood‐borne pathogen that produces flu‐like symptoms in infected individuals and is responsible for microcephaly and other neonatal birth defects. Despite this growing public health concern, the molecular mechanisms involved in ZIKV infection are still poorly understand. We have recently shown that African and South American derived ZIKV strains infect human endothelial cells in culture (Liu et al., Circ Res, 2016). Still, the role of the vasculature and endothelium during in vivo infection are not known. We investigated a role for the vasculature in ZIKV infection and hypothesize that ZIKV expression in infected animals will localize to vascular beds.We established ZIKV infection using an in vivo animal model of infection in 4‐week old C57Bl/6 mice. Mice received 6.4×106 plaque forming units (PFUs) of either the PRVABC59 or DAK strains of ZIKV, isolated in Puerto Rico and Senegal respectively. Mice were sacrificed at 5 days post‐infection and we used immunohistochemistry to detect ZIKV expression in various vascular beds including brain, liver, aorta and mesenteric. ZIKV was labeled using a novel murine monoclonal antibody D1‐4G2‐4‐15 against the viral coat protein E‐protein.At 5 days post‐infection (dpi), mice treated with the DAK strain have decreased body weight compared to Day 0, while mice treated with the PRV are resistant to this weight loss. At 5 dpi, both groups of mice have increased brain ZIKV viral loads. However, the viral load in DAK mice was four‐fold that of PRV‐treated mice. Mice treated with DAK show increased morbidity with 0% survival at 7 dpi while the PRV strain is non‐lethal up to 15 dpi. At 5 dpi, the ZIKV viral coat protein E protein was detectable in arteries and veins of the cerebral circulation from brains of mice treated with either ZIKV strain and co‐localized with the endothelial marker claudin‐5. Interestingly, cerebral capillaries were found to have the DAK ZIKA, whereas the PRV did not.The co‐localization of ZIKV with endothelial markers suggests a role in the pathology of in vivo ZIKV infection. These findings improve our understanding of the pathology of ZIKV infection and hint at potential strain variation that may be mediated by endothelium.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Bardoxolone activates cardiac Nrf2, increases antioxidant expression and lowers arterial pressure in rats with heart failure
Authors: Zhang Andi , Tian Changhai , Gao Lie , Zucker Irving H. 
Published: June 2021

Chronic heart failure (CHF) is associated with increased levels of oxidant stress in many tissues. High levels of reactive oxygen species (ROS) impairs cardiac, neural and renal function. Increased ROS in CHF is, in part, due to low levels of a variety of antioxidant enzymes. Many of these enzymes are regulated by the activity of the transcription factor Nuclear factor E2‐related factor 2 (Nrf2), which binds to antioxidant response elements (ARE) on multiple genes. Activation of Nrf2 has been shown to modulate a variety of disease states as well as several negative effects of the aging process. We hypothesized that pharmacological activation of systemic Nrf2 would provide beneficial hemodynamic effects in a rodent model of CHF. Male Sprague Dawley rats were subjected to left coronary artery ligation or sham surgery, and were divided into four groups (Sham+Vehicle, Sham+Nrf2 activator, CHF+Vehicle and CHF+Nrf2 activator) based on echocardiographic analysis 4 weeks post myocardial infarction. The Nrf2 activator, bardoxolone was administered daily for another 2 weeks by intraperitoneal injection (i.p) injection. Control animals were treated with the saline vehicle. Hemodynamics were evaluated by ventricular catheterization (Millar) and echocardiography (Vevo 2100). Animals were sacrificed, tissues taken and kept at −80 °C until analyzed. Our results demonstrated that Bardoxolone did not cause any changes in LV ejection fraction in either group (72.1±1.3 sham‐vehicle vs 73.0±1.2 sham‐bardoxolone; 32.9± 0.8 CHF‐vehicle vs 33.5±0.8 CHF‐bardoxolone). However, Bardoxolone significantly reduced LV systolic pressure and mean arterial pressure in CHF rats (LVSP; Vehicle 138.0±8.0 vs bardoxolone 117.0±3.9 mm Hg, p=0.04; MAP; Vehicle 97.8±2.9 vs bardoxolone 87.5±4.5 mm Hg, p=0.07). In addition, Bardoxolone had no effect on LVEDP or LV dp/dt max or min in rats with CHF. Molecular studies further revealed that In CHF rats Nrf2 mRNA was increased in the non‐infarcted areas of the heart by 2.5‐fold. Importantly, both mRNA and protein levels of NAD(P)H dehydrogenase [quinone] 1 (NQO1), a known target for Nrf2, was significantly increased by bardoxolone. Co‐IP experiments in skeletal muscle also showed that Bardoxolone reduced NF‐kB and increased Nrf2 binding to the CREB‐Binding Protein, respectively. These data suggest that activation of Nrf2 may provide beneficial antioxidant effects on cardiac muscle in CHF and reduces afterload. The mechanisms for the peripheral effects have not been determined.Support or Funding InformationSupported by PO1 HL 62222 and an APS summer undergraduate fellowshipThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.