bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood‐based biomarkers as early predictor of mortality in experimental hemorrhagic shock
Authors: Shi Jianru , Dai Wangde , Carreno Juan , Hale Sharon L. , Kloner Robert A. 
Published: June 2021

BackgroundHemorrhagic shock remains a major cause of mortality and morbidity on the battle field. Appropriate use of blood‐based biomarkers is clinically important to manage patients and predict death versus survival in the early stage of hemorrhagic shock. In continuation of our previous study, blood‐based early biomarkers were tested in 94 rats undergoing hemorrhagic shock.MethodsSprague Dawley rats (both genders) were anesthetized with either intraperitoneal ketamine and xylazine or with Isoflurane. Rats were intubated and ventilated with room air. After heparinization, hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure of 30 or 40 mmHg for 30 minutes, 35 minutes, 45 minutes, or 60 minutes and then the shed blood was reinfused. Arterial blood samples were collected 1–3 hours after resuscitation with shed blood. The rats were allowed to survive for 6 weeks.ResultsThe pH, bicarbonate (HCO3), oxygen saturation (SO2%), base excess and calcium levels were significantly lower in rats that died (n=63) versus survivors (n=31). Rats that died had significantly elevated anion gap, potassium, sodium and chloride levels compared to rats that survived (Table). PO2, PCO2, hematocrit, hemoglobin, glucose and lactate levels are comparable between rats that died versus survived.ConclusionsThe low pH, HCO3, SO2%, base excess and calcium coupled with high anion gap and high potassium, sodium and chloride levels may help predict long term prognosis in hemorrhagic shock.Support or Funding InformationThis work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program under Award NO. W81XWH‐16‐1‐0606. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by Department of Defense.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cerebral microhemorrhages impair gait coordination in mice
Authors: Tarantini Stefano , Yabluchanskiy Andriy , Fulop Gabor Aaron , O'Connor Daniel , Sonntag William Edmund , Csiszar Anna , Ungvari Zoltan 
Published: June 2021

Impairment in gait coordination and the consequent risk of falling are important problems in the rapidly aging population of the Western world: clinically diagnosable gait abnormalities affect approximately 35% of adults over age 70. While musculoskeletal mechanisms and processes have been extensively studied, factors affecting central neural control of gait coordination in older adults without overt neurological diseases are much less understood. Recent studies raise the possibility that in addition to causing cognitive decline, age‐associated cerebromicrovascular pathologies also contribute to mobility disability. However, the specific microvascular mechanisms underlying the loss of gait coordination in aging are not completely understood. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and cause focal disruption of neuronal networks. While there is growing evidence that CMHs predict cognitive impairment, the association between CMHs and gait abnormalities have not been investigated. The present study was designed to provide proof‐of‐concept that CMHs are causally linked to progressive gait dysfunction. To achieve this goal, we adapted a model of hypertension‐induced CMHs in mice (treatment with angiotensin II plus the NO synthase inhibitor L‐NAME). Computerized gait analysis was performed daily (Noldus CatWalk). CMHs were verified histologically. Mice with CMHs showed significantly altered gait function as measured by stride length, stride time and stride length variability, changes in phase‐dispersion and gait speed. CMH burden also correlated changes in the regularity index (a measure of inter‐paw coordination). Collectively, hypertension‐induced CMHs result in detectable impairment of gait function in mice. Further studies to analyze association of CMHs with gait abnormalities in human patients are warranted.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on AgingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increasing endothelial adenosine via adenosine kinase inhibition augments conducted vasodilation in HFpEF
Authors: Davila Alec C. , Christiansen Stephanie , Patel Vijay , Kamath Vinayak , Li Jie , Su Huabo , Huo Yuqing , Weintraub Neal , Bagi Zsolt 
Published: June 2021

Dysfunction of coronary microvessels impairs myocardial perfusion, a pathology that has been recently implicated in the development of heart failure with preserved ejection fraction (HFpEF). We sought to determine if HFpEF exerted effects on conducted vasodilation, which critically coordinates vascular resistance longitudinally across the arteriole wall to ensure adequate tissue perfusion. Obese and hypertensive ZSF1 rats, a model of HFpEF, develop left ventricular (LV) hypertrophy and diastolic dysfunction by 20‐wk of age. Conducted vasodilation was examined in isolated and pressurized skeletal muscle arterioles of lean and obese ZSF‐1 rats before (14–16 wk) and after (20–22 wk) the development of LV diastolic dysfunction. In addition, we obtained human coronary arterioles from patients with or without HFpEF. Conducted vasodilation was induced by focal application of acetylcholine, while arteriolar diameter was measured at local and remote sites (500 and 1000 μm away from the focal stimulation) using videomicroscopy. We found a significantly reduced conducted vasodilation in obese ZSF1 rats, at 14–16 wk and 20–22 wk of age, and similar results in HFpEF patients. Impaired conducted vasodilation was associated with an increased expression of adenosine kinase (ADK), the major adenosine metabolizing enzyme. Increasing intracellular adenosine levels via a pharmacological ADK inhibitor, ABT‐702, restored conducted vasodilation in isolated arteries of ZSF1 rats and HFpEF patients. Moreover, mice with endothelium‐specific deletion of ADK exhibited enhanced conducted vasodilation and were protected against the development of transverse aortic constriction‐induced LV hypertrophy and diastolic dysfunction. We concluded that increased vascular ADK expression lead to an impaired conducted vasodilation in HFpEF, which can be restored by increasing endothelial adenosine levels via ADK inhibition.Support or Funding InformationNational Institute of Aging (R01AG054651) and the American Heart Association (GRNT33680171)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Regression of pressure overload‐induced cardiac hypertrophy by TETA‐mediated myocardial copper supplementation in rats
Authors: Liu Jiaming , Liu Yinjie , Sun Xiaorong , Fan Suzhen , Ding Xueqin , Qiu Liying , Han Pengfei , Kang Y. James 
Published: June 2021

Sustained pressure overload leads to cardiac hypertrophy and copper efflux from the heart. Dietary copper supplementation replenishes copper in the heart and reverses cardiac hypertrophy. On the contrary, a copper selective chelator, trientine (TETA), reverses left ventricular hypertrophy associated with diabetes. The present study was undertaken to test the hypothesis that TETA functions as a copper chaperone delivering copper to the heart leading to regression of cardiac hypertrophy. Adult male Sprague‐Dawley rats were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Eight weeks after the surgery cardiac hypertrophy was developed and myocardial copper was reduced. TETA was then administrated by gavage at two different doses (21.9 mg/kg·day and 87.6 mg/kg·day) for six weeks. The results showed that at lower dose, TETA replenished copper contents in the heart, accompanied by a decrease in blood plasma and an increase in urine of copper concentrations. At higher dose, TETA did not replenish copper contents in the heart, but markedly increased copper concentrations in the urine, along with a decrease in serum copper concentrations. Corresponding to myocardial copper repletion, lower dose TETA reversed cardiac hypertrophy, as judged by a reduction in the left ventricle wall thickness (LVAWd and LVPWd) and a decrease in the heart size (heart weight/tibia length), and diminished cardiac fibrosis, as reflected by a decrease in collagen I content. TETA at higher dose not only did not regressed cardiac hypertrophy, but caused cardiac hypertrophy in sham‐operated rats. This study demonstrates that TETA, at lower dose, functioned as a copper chaperone delivering copper to the heart of copper deprivation and, at higher dose, simply remained its chelator function removing copper from the body by urinary excretion.Support or Funding InformationSupported by National Science Foundation of China (81230004 and 81300109).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Ryanodine Type 2 Receptors in Elementary Ca2+ Signaling in Arteries and Vascular Adaptive Responses
Authors: Kassmann Mario , Szijártó István András , García‐Prieto Concha F. , Fan Gang , Schleifenbaum Johanna , Anistan Yoland‐Marie , Tabeling Christoph , Shi Yu , le Noble Ferdinand , Witzenrath Martin , Huang Yu , Markó Lajos , Nelson Mark T. , Gollasch Maik 
Published: June 2021

ObjectiveCardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor. Resistance arteries can adapt their vessel diameter independently by pressure and by flow. Ryanodine receptors (RyRs) are major Ca2+ release channels in the sarcoplasmic reticulum (SR) membrane of myocytes contributing to contractility. Vascular smooth muscle cells (VSMCs) exhibit three different RyR isoforms (RyR1, 2, 3), but the impact of individual RyR isoforms on vascular adaptive responses is largely unknown.MethodsWe generated tamoxifen‐inducible smooth muscle cell (SM) specific RyR2 deficient mice and tested the hypothesis that VSMC RyR2s play a specific role in elementary Ca2+ signaling and adaptive vascular responses to vascular pressure and/or flow.ResultsTargeted deletion of the Ryr2 gene resulted in a complete loss of SR released Ca2+ sparks and the associated Ca2+ activated potassium (BKCa) channel currents, leading to increased myogenic arterial tone in peripheral arteries and systemic blood pressure. RyR2 deficiency enhanced the pulmonary artery pressure response to sustained hypoxia, but had no effect on flow‐dependent effects, including blood flow recovery in ischemic hind limbs.ConclusionOur results identify a specific contribution of RyR2 in mediating VSMC Ca2+ sparks relevant for regulating myogenic tone (systemic circulation) and arterial adaptation in response to changes in pressure (hypoxic lung model), but not flow. VSMC expressed RyR2 deserves scrutiny as a therapeutic target for the treatment of vascular responses in hypertension and chronic vascular diseases.Support or Funding InformationThis study was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) to M.G and M.W. (SFB‐TR84 C3 and C6), and the Deutsche Akademische Austauschdienst (DAAD) to M.G. and I.S, and the NIH (R37 DK053832, R01 HL121706, PO1 HL095488, R01 HL131181), Fondation Leducq, and the Totman Medical Research Trust to M.T.N., and by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research) to M.G. and M.K. We thank Dr. Kirill Essin for help in Ca2+ spark recordings using line scan imaging. CFG‐P is recipient of Ministerio de Educación Cultura y Deporte, Fundación San Pablo‐CEU and Banco Santander fellowships.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial cell PKD2 (TPP1) channels are essential for flow‐mediated vasodilation
Authors: Mackay Charles E. , Fernandez‐Pena Carlos , Bulley Simon A. , Jaggar Jonathan H. 
Published: June 2021

The endothelium detects shear stress generated by blood flow and transduces this mechanosensory signal to regulate arterial function. Intravascular flow stimulates an increase in arterial diameter, a process termed flow‐mediated vasodilation. The underlying mechanisms by which endothelial function is regulated by flow are poorly understood. Endothelial cells (ECs) express several non‐selective cation channels, including PKD2 (also termed TRPP1), but their involvement in flow‐mediated vasodilation is unclear. Here, we generated novel inducible, endothelial cell‐specific PKD2 knockout (PKD2endo−/−) mice to examine the functional significance of this channel in flow‐mediated vasodilation in resistance‐size mesenteric arteries. Immunofluorescence in intact arteries confirmed that PKD2 was present in endothelial cells of PKD2fl/fl mice, but absent in endothelial cells of PKD2endo−/− mice. Pressure (80 mmHg)‐ and depolarization (60 mM K+)‐induced vasoconstriction and passive diameter were similar in PKD2fl/fl and PKD2endo−/− arteries. In contrast, vasodilation to intravascular flow (15 dyn/cm2) in PKD2endo−/− arteries was ~20 % of that in PKD2fl/fl arteries. Endothelium denudation abolished flow‐mediated vasodilation. L‐NNA, a nitric oxide synthase (NOS) inhibitor, reduced flow‐mediated vasodilation by ~30% in PKD2fl/fl arteries. In contrast, TRAM 34 and apamin, IK and SK channel blockers respectively, did not alter flow‐mediated vasodilation. Microelectrodes were used to measure the membrane potential of pressurized, myogenic arteries. In the absence of luminal flow, the membrane potential of PKD2fl/fl and PKD2endo−/− arteries was similar (~−43 mV). Flow hyperpolarized PKD2fl/fl arteries by ~ 6.8 mV, but PKD2endo−/− arteries by only ~1.2 mV, an attenuation of 82 %. Taken together, our data suggest that flow stimulates PKD2 channels in endothelial cells, leading to membrane hyperpolarization, NOS activation and vasodilation.Support or Funding InformationNIH/NHLBIThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Knocking Out Endothelial TRPV4 Channels Enhances Vasoconstriction and Exacerbates Endothelial Dysfunction in Low‐Flow Vascular Injury
Authors: McFarland Stuart Joseph , Taylor Mark S. , Weber David S. 
Published: June 2021

Atherosclerosis remains a leading killer of men and women. It is associated with reduced blood flow, progressive endothelial dysfunction and vascular remodeling. Preventing pathologic endothelial changes is crucial for stopping the disease. Transient receptor potential cation channels (TRPV4) play a key role in endothelial responses to shear stress and local mediators by controlling dynamic endothelial Ca2+ signals. In the current study, we assessed the specific impact of endothelial TRPV4 channels on carotid artery function in both wild type (WT) control and endothelial‐specific TRPV4 knockout transgenic mice (KO). Following tissue harvest, carotid arteries were cut into rings for Isometric force myography. Depolarization‐induced contractions (60 mM KCl) were larger in KO than WT arteries (1.14 ± 0.14 mN vs. 0.52 ± 0.08 mN, P<0.0005, N=6) and a similar trend was noted for contractions induced by the α1 adrenergic receptor agonist phenylephrine (0.68 ± 0.12 mN vs. 0.43 ± 0.08 mN, P<0.1, N=6). The calculated EC50 indicated no significant difference (1.7×10−7 vs 1.5×10−7 M, n=6) in phenylephrine sensitivity. Net relaxation to acetylcholine was increased in KO vs. WT but EC50 values were not significantly different (5.5×10−7 vs 5.9×10−7, n=6). Using confocal imaging, endothelial Ca2+ was evaluated in carotid artery segments that were cut open longitudinally. The dynamic Ca2+ events that drive endothelium dependent vasorelaxation were altered in KO vs. WT arteries, exhibiting a lower frequency of these events but also events with larger mean amplitude and duration. A carotid artery partial ligation model was used to mimic the low flow predicted with atherosclerosis. Following 2 weeks of reduced flow, KO arteries demonstrated enhanced contractility and impaired ACh‐induced relaxation compared to similarly ligated WT arteries. Overall, our findings suggest that loss of endothelial TRPV4 channels inherently augments vasoconstriction and exacerbates endothelial dysfunction under conditions of chronic low flow.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
NaHS Induced ANP Secretion via PI3K/Akt/NO/cGMP and KATP Channel Pathway
Authors: Yu Lamei , Park Byung Mun , Kim Suhn Hee 
Published: June 2021

The third gasotransmitter, hydrogen sulfide (H2S), is related to the pathogenesis of cardiovascular diseases. However, it's still not clear about the relation between H2S and cardiac hormone, atrial natriuretic peptide (ANP). The purpose of this study is to investigate the effects of H2S donor on ANP secretion and seek its mechanism using normal and isoproterenol (ISP)‐treated hypertrophied rat atria. Different doses of H2S donors were perfused into isolated beating rat atria, and atrial pressure and ANP secretion were measured. NaHS (1, 10, 50, 100 μM) augmented high stretch‐induced ANP secretion and decreased systolic atrial pressure (SAP) dose‐dependently. Pretreatment with an inhibitor or antagonist for phosphatidylinositol 3‐kinase (PI3K; wortmannin), protein kinase B (Akt; API‐2), nitric oxide synthase (NOS; L‐NAME), soluble guanylyl cyclase (sGC; ODQ), and KATP channel (glibenclamide) blocked the augmentation of ANP secretion induced by NaHS. The high stretch‐induced ANP secretion was stimulated by Na2S but was not changed by GYY4137 and sodium thiosulfate. H2S synthesis enzyme inhibitor (DL‐propargylglycine, PAG) did not show any significant changes in atrial parameters. However, the response of ANP secretion to NaHS markedly attenuated and PAG suppressed ANP secretion in ISP‐treated rat atria. The expression of eNOS protein was decreased but the expression of cardiomyocyte‐specific H2S producing enzyme, cystathione γ‐lyase, was not changed in ISP‐treated rat ventricles. These findings clarify that NaHS stimulates ANP secretion through PI3K/Akt/NO/cGMP and KATP channel pathway. The modification of ANP secretion by NaHS and H2S synthesis enzyme inhibitor suggests the possible role of endogenous H2S in the pathogenesis of cardiac hypertrophy.Support or Funding InformationSupported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NO 2017‐R1A2B‐4002214).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Exercise and Peripheral Opioid Receptor Stimulation on Anxiety‐Like Behaviors in a Rat Model of Chronic Pain
Authors: Stocks Silas , Daniels Abigale B. , Ford Caleb M. , Horton Molly , Williams Emily R. , Leal Anna K. 
Published: June 2021

Patients with fibromyalgia are more likely to suffer from anxiety. In the acidic saline‐induced chronic pain model, rats exhibit long‐lasting, wide‐spread pain along with anxious behaviors. Exercise training has been shown to decrease pain in both patients with fibromyalgia and in this rat model of chronic pain; however the effect of exercise on anxiety and the contribution of peripheral opioid receptors to this effect are unknown. All experiments were performed in female Sprague‐Dawley rats that demonstrated chronic widespread pain due to acidic saline injections and all rats underwent moderate‐intensity treadmill training (4 weeks; 5 days/week; 30 min/day at 15 m/sec). Anxiety‐like behaviors were determined using the open field test. Control rats (n=4) were observed in the open field (90 × 90 cm) for two minutes before (PRE) and after (POST) each exercise bout. Time spent moving was recorded: decreased motility demonstrated anxiety. A separate group of rats (NAL; n=5) received injections of the nonspecific opioid receptor antagonist naloxone (120 μg in 100 μL saline) in both gastrocnemius muscles ten minutes prior to treadmill running in addition to open field testing. Results showed that treadmill training alone had no effect on control rats' average time spent moving in the open field: 32.5 ± 4.2 s (PRE) and 31.2 ± 4.4 s (POST) for week 1; 35.1 ± 4.2 s (PRE) and 31.7 ± 3.8 s (POST) for week 2; 32.7 ± 4.3 s (PRE) and 38.3 ± 4.8 s (POST) for week 3; and 35.6 ± 4.6 s (PRE) and 34.5 ± 3.1 s (POST) for week 4. However, NAL rats demonstrated increased anxiety‐like behaviors indicated by decreased average time spent moving for all weeks tested: 25 ± 3.9 s (PRE) and 14.2 ± 3.2 s (POST) for week 1; 34.6 ± 3.4 s (PRE) and 18.9 ± 2.8 s (POST) for week 2; 35 ± 4.1 s (PRE) and 16.5 ± 3.2 s (POST) for week 3; and 38 ± 4.5 s (PRE) and 17.9 ± 2.9 s (POST) for week 4. In NAL rats, PRE and POST times were significantly different for all four weeks (p<0.05). PRE times were not different between control and NAL groups, however, POST times were significantly different between control and NAL groups for all weeks. Our data suggests that endorphins released during exercise act on peripheral opioid receptors to reduce anxiety‐like behaviors associated with the exercise bout in a rat model of chronic pain. These findings support the use of exercise to reduce anxiety and chronic pain in people with fibromyalgia.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cyrotherapy Reduces Macrophage Infiltration and Inflammatory Mediators Following Muscle Injury
Authors: Rafferty Patrick , McMahon Katherine , Arrigale Marlena , Carpenter April 
Published: June 2021

Cryotherapy following muscle injury is a commonly used treatment in sports medicine. However, there are conflicting reports on the efficacy of cryotherapy to reduce inflammation. The infiltration of macrophages and macrophage produced growth factors are now considered important mediators of the healing process. The purpose of our study was to evaluate the effects of cryotherapy on inflammation associated with muscle regeneration in mice. Following BaCl2 injury, we observed a significant reduction in macrophage infiltration in mice that received cryotherapy (20 min of ice therapy every 2hr during consecutive 12 hr wake cycles) over a 48 hr period. qPCR analysis of mRNA expression for wnt proteins and inflammatory mediators revealed a statistically significant reduction in wnt 2b, 3, 5a, 11, 16 and NFk‐β, TNF‐α, TGF‐β, and IGF‐1. Given that wnt proteins are important during development of muscle and in many tissue regeneration models, we believe this supports the notion that the reduction in inflammation afforded by cryotherapy may correspond with a delay in muscle healing. Studies are ongoing to determine the long‐term effects of cryotherapy on macrophage‐mediated muscle regeneration and extracellular matrix remodeling.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.