bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of NADPH Oxidase (Nox)‐derived Reactive Oxygen Species (ROS) to Doxorubicin‐induced Cardiomyopathy Mediated by Regulator of G protein Signaling 6 (RGS6)
Authors: Chakravarti Bandana , Yang Jianqi , Luo Zili , Ahlers Katelin E. 
Published: November 2023

Oxidative stress, defined as an excess of reactive oxygen species (ROS) compared to antioxidant defenses, is implicated in the pathophysiology of heart failure. ROS play a critical role in regulation of cardiac myocyte apoptosis through control of redox‐sensitive signaling cascades and can also activate hypertrophic kinases, transcription factors and proteins involved in extracellular matrix remodeling. Nox proteins have emerged as major sources of ROS in the pathogenesis of myopathic changes associated with heart failure. RGS6 is a member of the RGS protein family of heterotrimeric G protein regulators. Our recent studies have identified an entirely novel signaling action of RGS6 as an upstream modulator of ROS‐dependent apoptosis in the heart. Mice lacking RGS6 are almost completely protected from ventricular ROS generation, cardiac myocyte apoptosis and loss of ventricular function in response to doxorubicin (Dox). We hypothesized that RGS6 is required for Nox‐dependent ROS production in cardiac myocytes induced by Dox and that it promotes apoptosis by a Nox‐ROS‐dependent mechanism. Nox2 and Nox4 are the major isoforms expressed in heart and are found in distinct subcellular locations. Plasma membrane bound Nox2 is critical for cardiac remodeling and contractile dysfunction in response to Dox. Here, we show increased Nox activity and a trend for increases in Nox 2 and Nox4 mRNA in hearts of wild type (WT) mice 5 days following Dox administration, as reported previously. These responses to Dox were not observed in mice lacking RGS6 suggesting that RGS6 is required for Dox‐induced Nox activation and possibly for increases in Nox mRNA expression in heart. In light of these findings, we examined the effects of Dox on cell death, caspase 3 activity and Nox activity in adult cardiomyocytes derived from WT, RGS6−/−, p47−/− (Nox2 subunit) and RGS6−/−; p47−/− double knockout mice. Individual loss of RGS6 or p47 blocked Dox‐induced increases in cell death, caspase 3 activity and Nox activity while their combined loss had no effect. These results provide new evidence that RGS6 is a critical upstream modulator of Nox‐derived ROS contributing to Dox‐induced cardiomyopathy. The mechanism(s) by which RGS6 modulates Nox activity in heart and the importance of the RGS6‐Nox‐ROS signaling cascade in oxidative stress‐induced cardiomyopathies are currently under investigation.Support or Funding InformationSupported by NIH CA161882, AHA 14GRNT20460208 (RAF) and AHA 11SDG7580008 (JY).
Smooth Muscle/Endothelial KIR Channels Modulate Cell‐to‐cell Communication in Cerebral Arteries
Authors: Gonzalez Maria Sancho , Samson Nina , Hald Bjorn Olav , Hashad Ahmed , Marrelli Sean , Brett Suzanne , Welsh Donald Gordon 
Published: November 2023

Global blood flow control is enabled by the conduction of charge along arteries. The distance over which electrical phenomena spread is governed by 3 factors, one being the ionic properties of vascular cells. In this study, we determined the role of inward rectifying K+ channels (KIR) in setting membrane conductance and charge spread along the arterial wall. Small middle cerebral arteries (~100 μm diameter) from hamster were probed with a standard conduction protocol. A focal KCl stimulus elicited a constrictor response that conducted robustly, with a decay constant of ~0.4 μm/100μm vessel length. Selective inhibition each K+ channel class had no effect on conduction, the exception being Ba2+ blockade of KIR, which facilitated decay (~1.6 μm/100μm vessel length). Patch clamp electrophysiology and Q‐PCR highlighted the presence of a KIR current in smooth muscle comprised of KIR2.1/2.2 subunits. The incorporation of this current into an electrical model revealed that it was too small to account for the change in conduction decay; consequently another KIR current must be present. Electrophysiology and Q‐PCR confirmed a second KIR current in the endothelium. Computational modeling subsequently confirmed that inhibiting both currents had a greater effect on conduction decay, the result of a sizable voltage shift increasing feedback from voltage dependent‐ and Ca2+ activated K+ channels. In summary, our observations indicate that KIR channels are present in endothelial and smooth muscle cells, and together these K+ conductances can tune electrical communication.Support or Funding InformationSupported by CIHR
Estimating Blood Flow in Skeletal Muscle Arteriolar Trees Reconstructed from In Vivo Data
Authors: Goldman Daniel , Saleem Amani H. , Al‐Khazraji Baraa K. , Jackson Dwayne N. 
Published: November 2023

BackgroundOur group uses both computational modeling and intravital videomicroscopy to study the regulation of blood flow in the microcirculation of skeletal muscle. Although we are able to obtain nearly complete arteriolar network structure from in vivo experiments, obtaining complete hemodynamic information is much more difficult and time‐consuming. It is also difficult to obtain the full boundary data needed to directly calculate microvascular blood flow and hematocrit distributions. Therefore, the objective of the present work was to develop a computational model that could accurately predict blood flow in skeletal muscle arteriolar trees in the absence of complete boundary data.MethodsWe used arteriolar trees in the rat gluteus maximus muscle (GM) that were reconstructed from montages obtained via intravital videomicroscopy, and incorporated a recently published method for approximating unknown boundary conditions into our existing steady‐state model of two‐phase blood flow. For varying numbers of unknown boundary conditions, we used the new flow model and GM arteriolar geometry to approximately match red blood cell (RBC) flows corresponding to experimental measurements.ResultsWe showed that this method gives errors that decrease as the number of unknown boundary conditions decreases. We also showed that specifying total blood flow into the arteriolar tree decreases the mean RBC flow error and its variance. By varying target values of pressure and wall shear stress required by the model, we showed that results are less sensitive to the target pressure, and we developed a method for estimating the optimal target shear stress.ConclusionWe have developed and validated a computational method that can accurately estimate RBC flow distribution in arteriolar trees in the absence of complete boundary data.Support or Funding InformationFunding: Natural Sciences and Engineering Research Council (NSERC) grant #R4081A03 awarded to DG, NSERC grant #R4218A03 awarded to DNJ, and NSERC CGS‐D Scholarship awarded to BKA.
Interventions Blunting Systemic Inflammation and Oxidant Stress Improve Depressive Symptoms and Vascular Function in a Model of Metabolic Syndrome
Authors: Sheets Whitney Jordan , Brooks Steven D , Chantler Paul , Frisbee Jefferson 
Published: November 2023

Metabolic syndrome (MetS) is a combination of physical ailments such as diabetes, hypertension, hyperglycemia, and hypertriglyceridemia. MetS is associated with increased likelihood for developing cardiovascular disease (CVD), the leading cause of death in the United States. A growing body of evidence has established CVD and MetS as risk factors for developing depression, raising questions about the physiological links between these highly prevalent conditions. This comorbidity has been observed preclinically in obese Zucker rats (OZR), which concurrently develop MetSyn and symptoms of depression with age. While several studies have sought to evaluate possible cardiovascular benefits of common antidepressants, such as SSRIs, little is known as to whether treating constituent pathologies of Metabolic Syndrome could have beneficial effects on depressive symptoms. The purpose of this study was to evaluate the efficacy of several commonly prescribed therapeutic agents towards improving vascular function and reducing depressive behaviors in adult OZR, and to identify potential mechanisms defining these effects. At 7–8 weeks of age, male OZR and lean control (LZR) animals received one of the following therapies for 9 weeks: anti‐hypertensive (captopril, hydralazine), anti‐diabetic (metformin, rosiglitazone), anti‐dyslipidemic (atorvastatin, gemfibrozil), anti‐oxidant (TEMPOL), or daily treadmill exercise training; at the conclusion of treatment, depressive symptoms, ex vivo arteriolar vascular reactivity, NO bioavailability, and plasma biomarkers of stress and inflammation were assessed in each animal. Of all treatments, exercise, atorvastatin, and TEMPOL were found to significantly improve depressive symptoms in OZR and restore vascular function in skeletal muscle arterioles. Further analysis revealed that these three interventions all reduced levels of plasma TNF‐α, nitrotyrosine, corticosterone, and thromboxane, in addition to improving NO bioavailability and vascular reactivity. Each of the other treatments improved at least their primary pathological target, but did so without improving depressive symptoms. These findings suggest that the pleiotropic benefits of atorvastatin, TEMPOL, and exercise‐ specifically, anti‐inflammatory and anti‐oxidant effects‐ may contribute to improving depressive symptoms. Additionally, these results imply a possible cardiovascular etiology for depression, and raise the possibility that coupling antidepressant therapy with a drug such as atorvastatin could lead to improved outcomes for patients with depression.Support or Funding InformationAHAWVU CCRS
Contractile Pericytes Determine the Direction of Blood Flow at Capillary Bifurcations
Authors: Gonzales Albert L , Longden Tom A , Shui Bo , Kotlikoff Michael I , Nelson Mark T 
Published: November 2023

Pericytes cover most of the surface area of brain capillaries, and yet their role in controlling cerebral blood flow is controversial. Although pericytes have a distinct morphology from vascular smooth muscle, pericytes at the first and second capillary junctions downstream of the terminal arteriole exhibit many of the same excitation‐contraction coupling molecules as smooth muscle, e.g. smooth muscle a‐actin, Cav1.2 and TRPM4 (from immunohistochemistry). We tested the hypothesis that junctional pericytes are capable of controlling the direction of flow in the capillary bed, insuring efficient delivery of blood to downstream neurons. Using a novel transgenic mouse expressing a genetically encoded Ca2+ biosensor in contractile pericytes and smooth muscle (acta2‐GCaMP5‐mCherry), we observed IP3R‐ and Cav1.2‐, but not ryanodine receptor‐mediated, Ca2+ events. Using in vivo multiphoton microscopy, we observed a higher frequency of Ca2+ events in pericyte projections covering the branch with lower red blood cell (RBC) flux at capillary bifurcation. The thromboxane receptor agonist, U46619, deferentially increased Ca2+ signaling in the pericytes covering the two branches such that less contracted branch increased its Ca2+ signaling and RBC flux was reduced to the level of other branch, i.e. flux was normalized in two branches. These data support the concept that pericytes play a role in controlling the directional flow of blood within the capillary bed.Support or Funding InformationTotman Medical Research Trust, Foundation Leducq, AHA 14POST20480144, NIH T32HL‐007594, P01HL‐095488, R37DK‐053832, R01HL‐121706, and R24HL‐120847
Sphingosine 1‐Phosphate (S1P) Attenuates Combined Acute Alcohol Intoxication and Hemorrhagic‐Shock/Resuscitation‐Induced Microvascular Hyperpermeability in Rat Mesentery
Authors: Doggett Travis Matthew , Alves Natascha G , Yuan Sarah Y , Breslin Jerome W 
Published: November 2023

Alcohol intoxication‐related injuries remain a significant clinical problem involving at least 38 million individuals and producing and estimated $223.5 billion health care cost burden in the US. In the emergency room, intoxicated trauma patients present with increased injury severity and are more hypotensive, a predictor of poor outcomes. We have previously demonstrated that acute alcohol intoxication causes microvascular hyperpermeability in vivo, and also exacerbates hemorrhagic shock/resuscitation‐ (HSR)‐induced microvascular leakage. In the current study, we tested the hypothesis that the barrier‐enhancing bioactive lipid Sphingosine 1‐Phosphate (S1P) can reverse the microvascular hyperpermeability and hypotension following combined acute alcohol intoxication and HSR. Carotid artery, jugular vein, and indwelling gastric catheters were surgically placed in anesthetized Sprague Dawley rats. Following 6–7 days recovery, conscious, unrestrained rats received 2.5 g/kg alcohol via the intragastric catheter, followed by HSR (fixed pressure of 40 mm Hg for 1 h, followed by Lactated Ringers (LR), 40% i.v. bolus + 2x total blood volume removed infusion over 1 h). During resuscitation, the rats received 0.003, 0.03, or 0.1 mg/kg S1P within the LR fluid. Following the 1‐h resuscitation phase, the rats were anesthetized for intravital microscopy of the mesenteric microcirculation. FITC‐Albumin served as a tracer to determine extravasation, quantified by measuring integrated optical intensity (IOI) of the extravascular areas adjacent to postcapillary venules. The results show that by the end of the 1‐h fluid resuscitation period, the group receiving LR supplemented with 0.1 mg/kg S1P displayed significantly restored MAP compared to Alcohol/HSR (89.1 ± 3.6 mm Hg for Alcohol/HSR + 0.1 mg/kg S1P vs. 75.2 ± 3.1 mm Hg for Alcohol/HSR, p<0.05). This trend persisted during the subsequent intravital microscopy phase of the experiment (86.3 ± 3.3 mm Hg Alcohol/HSR + 0.1 mg/kg S1P vs. 68.3 ± 4.3 mm Hg Alcohol/HSR, p<0.05). In addition, 0.1 mg/kg S1P reduced the alcohol/HSR‐induced microvascular hyperpermeability by 50% (542.3 ± 58.4 IOI units for Alcohol/HSR + 0.1 mg/kg S1P vs. 1061.7 ± 142.1 IOI units for Alcohol/HSR, p<0.001). These data show that fluid resuscitation augmented with 0.1 mg/kg S1P ameliorates alcohol/HSR‐induced hypotension and microvascular hyperpermeability more effectively than standard fluid resuscitation. Overall, the data show promise for using fluid resuscitation augmented with S1P for improving circulation in traumatic injury patients.Support or Funding InformationSupported by NIH grants R01HL098215 and R21AA020049, and the ABMRF/Foundation for Alcohol Research.
Optimization of the Hemodynamic of the Kidney and Preservation of Glycocalyx During Kidney Transplantations ‐ A Combination of Fluid Therapy and Low Dose Norepinephrine
Authors: Eriksen Jonathan Kunisch , Moeslund Niels , Nielsen Lise Have , Petersen Jens Aage Kølsen , Jespersen Bente , Birn Henrik 
Published: November 2023

BackgroundDelayed Graft Function (DGF) is a common complication to kidney‐transplanted patients receiving a kidney from brain dead donors. The present study is designed to evaluate the influence of fluid therapy on kidney function and the preservation of the glycocalyx, during kidney transplantation using kidneys from brain dead donors.MethodA porcine prospective randomized animal study is performed. The recipients are randomized to either high volume fluid therapy or individualized goal directed fluid therapy (IGDT). The pigs are also randomized to either no Nor‐epinephrine (NE) or continuous low dose NE‐infusion.Brain death is achieved by inflating a 60cc urinary catheter inserted in the epidural space until the intracranial pressure exceeds the systolic pressure. After 4 hours of brain death the kidneys are perfused with “Bridge to life®” and removed and stored cooled at 4°C for at least 18 hours.The recipients are bilaterally nephrectomised and each gets one kidney. The recipient pigs are observed for 10 hours post‐reperfusion. Blood and urine samples are collected during this observation period. Biopsies are taken from the donor kidneys at baseline and after 3 hours of brain death, and in the recipient immediately after reperfusion and 10 hours post reperfusion.The kidney function will be evaluated using measured GFR (mGFR) and by studying the histology of the kidney using light microscopy.We plan to evaluate the glycocalyx degradation by analyzing blood for Syndecan‐1 and Heparan Sufalte using ELISA. Further to evaluate the histology, the biopsies will be studied in microscope, along with immunofluorescence evaluation of Syndecan‐1 for a semi‐quantitative measurement for glycocalyx.ResultsAs this is an ongoing study no results have yet been obtained.ConclusionWe hope to show a significantly better kidney function and glycocalyx preservation in the IGDT group, and even better in the group receiving NE.Support or Funding InformationThis Study is funded by the Novo Nordic fund.
Blunted Endothelial Dependent Vasodilation in the Cutaneous Microvasculature of College‐Aged African Americans
Authors: Patik Jordan C , Hurr Chansol , Christmas Kevin M. , Brothers R. Matthew 
Published: November 2023

African Americans (AA) have elevated risk for hypertension, insulin resistance, and cardiovascular disease compared to their Caucasian American (CA) counterparts. Previously, we have observed attenuated vasodilation in the cutaneous vasculature during local heating in young, healthy AA compared to CA. Impaired endothelium‐dependent vasodilation in response to acetylcholine (ACh) is present in other at‐risk populations, including aging, obesity, smokers, and hypercholesterolemics. Therefore, the aim of the current study was to test the hypothesis that AA have a blunted vasodilatory response to the ACh analog methacholine (MCh). Twenty‐three (12 AA, 11 CA) volunteers free of overt disease participated in the study. AA and CA groups were matched for age (21.5±1 vs 23.9±1 years, P=0.30), BMI (25±1 vs 23.8±1, P=0.31), and sex (AA: 6M/6F, CA:6M/5F). MCh was delivered via a sterile microdialysis fiber inserted in the dermal layer of the left forearm. MCh doses of 10−6, 10−5, 10−4, 10−3, 10−2, and 1M (mixed in lactated Ringer's) were infused into the skin for 6 min each dose at a rate of 2μL/min. Cutaneous red blood cell flux was measured via laser Doppler fluximetry (LDF) continuously and averaged over the last min of each dose. Local heaters were set to 33°C throughout the dose‐response protocol. Brachial blood pressure was taken during the last min of each dose on the contralateral arm. Cutaneous vascular conductance (CVC) at each dose was calculated as LDF/MAP and then normalized to each individual's maximal CVC during combined 44° heating and 28mM sodium nitroprusside infusion (CVCmax). Using normalized data, four parameter logistic dose response curves for each group were compared with an extra sum of squares F‐test with maximum constrained to 100 (%CVCmax). Including all parameters, AA and CA dose response curves were different (P<0.001). Log EC50 for AA was at a higher dose (−2.814±0.26) compared to CA (−4.434±0.19, P<0.001). Hillslope was not different between groups (P=0.33). Baseline values were also not different (AA: 10.37±5.26 %CVCmax vs CA: 15.02±4.27 %CVCmax, P=0.54). The results of this study indicate that a significantly greater dose of MCh is required to reach 50% of maximal vasodilation in healthy, young AA compared to CA. This pharmacological evidence supports earlier findings suggestive of impaired endothelium‐dependent microvascular function in AA.Support or Funding InformationInstitutional Start‐up funds from the University of Texas at Austin
Nox1 Deletion Rescues Microvascular Dysfunction in Obese Mice
Authors: Thompson Jennifer Anne , Mintz James , Fulton David J , Stepp David W 
Published: November 2023

ObjectiveTo investigate the role of Nox1 in the development of microvascular dysfunction in obesity.MethodsFour genotypes were generated by breeding Nox1 knock‐out (KO) mice with obese db/db mice: (HdbWnox1); lean Nox1 KO (HdbKnox1); obese (KdbWnox1); double KO (KdbKnox1). At 12 weeks of age, body composition was determined by NMR spectroscopy and fasting levels of lipids, glucose and HbA1c were measured. Glucose tolerance tests in conscious mice were generated after IP injection of a glucose load (2g/kg body weight). Mesenteric arteries were isolated and endothelium‐dependent responses to acetylcholine (Ach) (10−12–10−3 M) were assessed in the presence or absence of L‐NAME (inhibitor of nitric oxide synthase) or Tempol (superoxide dismutase mimetic).ResultsBody weight and % body fat were increased in obese (KW, KK) vs. lean (HW, HK) mice (p < 0.01), while there were no differences in KW vs. KK (% body fat, HW: 16.3 ± 2.5 %; KW: 61.2 ± 5.2 %; HK: 14.2 ± 1.2 %; KK: 50.3 ± 5.0 %). Likewise, fasting plasma glucose, HbA1c, insulin and triglyceride levels were elevated in obese mice (p < 0.01), with no differences between KW and KK. The area under the curve for glucose tolerance tests was increased by 67% in HW vs. KW and 60% in HK vs. KK (p < 0.05). KK and KW mice also exhibited similar reductions in oxygen consumption and carbon dioxide production (p < 0.01). Endothelium‐dependent responses to Ach were blunted by 48% in obese (KW) vs. lean (HW) (p < 0.01), yet similar between obese mice with Nox1 deletion (KK) and lean controls (HK). L‐NAME incubation reduced Ach responses in HW, HK and KK animals (p < 0.01), but had no influence in KW. Tempol had no impact on HW, HK and KK, but improved Ach responses in KW mice.ConclusionsImpaired endothelial function in the microvasculature of obese db/db mice appears to be related to vascular superoxide production. Deletion of Nox1 improved microvascular endothelial function in obese db/db mice without influencing the degree of adiposity, hyperglycemia or dyslipidemia. Therefore, Nox1 may be an effective target for the prevention of vascular disease in the metabolic syndrome.Support or Funding InformationDWS is supported by AHA‐GIA and NHLR01 98744; JAT supported by AHA 15POST25730006
Post‐exercise changes in endothelin‐1 in military veterans with respiratory complaints
Authors: Salcedo Pablo , Jiao Xilu , Chen Yang , Klein Jacquelyn C , Ndirangu Duncan , Condon Michael R , Falvo Michael J 
Published: November 2023

Post‐9/11 veterans frequently report respiratory symptoms following deployment to Iraq and Afghanistan, which may be related to deployment‐related exposures. Work from our clinic has observed evidence of pulmonary vascular dysfunction (i.e., normal spirometry and reduced lung diffusing capacity [DLCO])as a common abnormality in this population. The goal of the present study was to evaluate changes in endothelin‐1 (ET‐1), a key vascular regulator, before and after a maximal cardiopulmonary exercise test and determine its relationship with measures of pulmonary gas‐exchange. Seven post‐9/11 veterans(34.7±4.1 years) with a median deployment length of 13 months and dyspnea onexertion (5.6±1.2 Borg Scale), completed a modified Bruce protocol on amotorized treadmill. Pre and post‐exercise venous plasma concentrations of ET‐1 were obtained using sensitive ELISA. Pulmonary gas‐exchange was assessed during exercise (VE/VCO2 slope) and at rest (DLCO). Baseline concentrations of ET‐1(1.04±0.2 pg/mL) were similar to post‐exercise levels (0.93±0.3; p=0.32), with three individuals demonstrating an exercise‐induced increase. The change in ET‐1 (−10.3±23.4%) was associated with exercise ventilatory efficiency (VE/VCO2 slope; r =0.77; p = 0.04), but was not associated with DLCO. However, we observed a mild reduction in DLCO (<85% predicted) in 4 veterans and normal DLCO (>85%) in the remaining group of individuals. Atrend for higher concentration of ET‐1 was observed (1.48±0.5 vs. 0.93±0.03pg/mL; p=0.08) in those with low DLCO (78.8±0.04%) versus normal DLCO (93.9±0.03%). The present study demonstrated that exercise‐induced changes in ET‐1 were associated with inefficient exercise ventilation, and individuals with reduced gas‐exchange at rest exhibit higher plasma levels of ET‐1. Future studies may consider investigating ET‐1 and pulmonary gas‐exchange in deployed veterans presenting with unexplained dyspnea.Support or Funding InformationVA RR&D 1I21RX001079‐01