bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of C‐reactive protein on Band 3 protein function in human erythrocytes
Authors: Morabito Rossana , Remigante Alessia , Spinelli Sara , Vitale Giulia , Scarfì Giuseppa , Dossena Silvia , Marino Angela 
Published: June 2021

C‐reactive protein (CRP) has a functional role in the inflammatory process and its concentration increases in circulation during inflammatory events. Transcriptional induction of the CRP gene mainly occurs in hepatocytes in the liver in response to increased levels of inflammatory cytokines, especially interleukin‐6 (IL‐6), therefore CRP is used as a clinical marker of inflammation. Elevated serum CRP levels are related to different inflammatory diseases such as cholecystitis, cardiovascular disease, cancer, type 2 diabetes, appendicitis and pancreatitis. The present study addressed the impact of CRP on Band 3 protein (B3p) function in human erythrocytes. The activity of B3p, mediating Cl−/HCO3− exchange through erythrocytes membrane, can be monitored by measuring the rate constant for SO4= uptake. Blood was withdrawn from both patients with acute inflammation (13 ♀, 9 ♂, age range 28–75 years) and healthy volunteers (10 ♀, 10 ♂, age 28–70 years). CRP levels higher than 8 mg/L were considered as a strong predictor of inflammatory disease and the rate constant for SO4= uptake was measured by a turbidimetric method. Elevated serum CRP levels induced a significant increase in both anion exchange capability through B3p and in SO4= trapped by the cells with respect to control (healthy volunteers). Once serum CRP levels in patients with acute inflammation were brought back to control values, anion exchange capability through B3p was restored. The present findings show that: i) measurement of the rate constant for SO4= uptake is a suitable tool to monitor the effect of elevated serum CRP levels on human erythrocytes due to acute inflammation; ii) high CRP levels seem to accelerate anion exchange capability through B3p; iii) inflammation remission seems to correspond to B3p function restoration. Future studies will evaluate whether this acceleration may depend on an altered Bp3 conformation possibly affecting B3p crosslink with Hb, or on altered oxidative and phosphorylative signaling on B3p function, in an attempt of better understanding the impact of inflammation processes on erythrocytes homeostasis.Support or Funding InformationNoneThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ablation of Na+/H+ exchanger‐3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis
Authors: Stone Sydney L , Bonamer John P , Ruwe T Alex , Azucenas Corbin R , Shawki Ali , Mackenzie Bryan 
Published: June 2021

Iron deficiency is the most prevalent micronutrient deficiency worldwide. Meanwhile, several common hereditary disorders result in iron overload (hemochromatosis) and subsequently liver disease, cardiomyopathy, and endocrine disorders. Since there exists no regulated mechanism for the excretion of iron, systemic iron homeostasis is achieved by tightly regulating iron absorption. We have demonstrated that the H+‐coupled divalent metal‐ion transporter‐1 (DMT1) is essential for the uptake of nonheme iron at the apical membrane of intestinal enterocytes [Shawki A et al (2015) Am J Physiol Gastrointest Liver Physiol 309, G635–G647]. DMT1 is a validated therapeutic target in hereditary hemochromatosis. More recently, we identified a role for the intestinal brush‐border Na+/H+ exchanger‐3 (NHE3) in driving iron absorption by generating the H+ gradient to energize DMT1 [Shawki A et al (2016) Am J Physiol Gastrointest Liver Physiol 311, G423–G430]. Here we tested the hypothesis that pathological iron loading depends on the activity of NHE3. We examined the effects of ablating NHE3 on the iron‐overload phenotype of the Hfe mouse model of hereditary hemochromatosis. We crossed the NHE3 and Hfe knockout lines (on the FVB/N background) and examined (at age ≈ 120 d) hematological variables, and tissue and blood iron status in male and female offspring fed a standard diet (NIH‐07). The increased nonheme iron observed in the livers of Hfe‐null mice relative to wildtype mice was absent in the double null (Hfe−/− | NHE3−/−) (n = 89, 2‐way interaction P < 0.001), an effect that did not differ by sex (no 3‐way interaction, P = 0.54). Liver histology, using Perls' Prussian blue stain to detect iron deposits, supported this finding. NHE3 knockout also normalized serum iron levels in the Hfe null. Our data reveal that ablation of NHE3 prevents iron loading in the Hfe mouse model of hereditary hemochromatosis, and present the possibility of targeting intestinal NHE3 in the treatment of iron overload.Support or Funding InformationNIH grants R01 DK080047, R01 DK107309, P30 DK078392, and R25 HL115473, and the American Physiological SocietyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chemokine (C‐X‐C motif) receptor 4 (CXCR4) activation in rat mesenteric artery myocytes is linked to suppression of Kv7 potassium channel activity
Authors: Byron Kenneth L. , Brueggemann Lyubov I. , LaPorte Heather , Majetschak Matthias 
Published: June 2021

Chemokine (C‐X‐C motif) receptor 4 (CXCR4) expressed in arterial smooth muscle cells was recently implicated in the regulation of blood pressure. As a part of a heteromultimeric receptor complex with atypical chemokine receptor 3 and α1‐adrenergic receptors, CXCR4 modulates α1‐adrenergic signaling and function in vascular smooth muscle cells. Furthermore, activation of CXCR4 was found to sensitize rats to α1‐adrenergic receptor‐mediated blood pressure elevation. In neurons, α1‐adrenergic receptor activation has been linked to suppression of M‐currents mediated by Kv7 voltage‐gated potassium channels. Suppression of Kv7 currents has also been implicated as a mechanism of vasoconstrictor signal transduction downstream of Gq/11‐coupled receptor activation in arterial smooth muscle cells. We observed that the CXCR4 agonists CXCL12 (SDF‐1α, 10 nM and 100 nM) and ubiquitin (100 nM and 1 μM) significantly and dose‐dependently inhibit Kv7 potassium currents in freshly isolated mesenteric artery smooth muscle cells (MASMCs) by up to 50%. Pretreatment of MASMCs with the CXCR4 antagonist AMD3100 (1 μM) prevented inhibition of Kv7 current by CXCL12 and ubiquitin. Moreover, proximity ligation assays provided evidence for direct interactions of CXCR4 with Kv7.5 channel α‐subunits in MASMCs. Our findings suggest that Kv7 potassium channels are downstream effectors of CXCR4 receptor activation in arterial smooth muscle cells.Support or Funding InformationThe project described was supported by R01GM107495 (M. Majetschak, PI).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of Acute Antioxidant Administration on Inflammation and Vascular Function in Heart Failure with Preserved Ejection Fraction
Authors: Ratchford Stephen M , Clifton Heather L , Gifford Jayson , LaSalle David Taylor , Thurston Taylor S , Bunsawat Kanokwan , Theisen Jeremy , Richardson Russell S , Wright Josephine B , Ryan John J , Wray D Walter 
Published: June 2021

BackgroundOne of the many unique features of heart failure with preserved ejection fraction (HFpEF) is the presence of multiple comorbidities, many of which are characterized by a pro‐inflammatory and pro‐oxidant state which may impair vascular function. This axis of inflammation, oxidative stress, and vascular function has been well described in other patient populations, whereby increases in reactive oxygen species lead to eNOS uncoupling, reduced nitric oxide (NO) bioavailability, and ultimately, impaired endothelium‐dependent vasodilation. Though there are many potential strategies for combating the damaging effects of inflammation and oxidative stress on peripheral vascular function, antioxidant (AO) administration has emerged as a simple, but effective, approach. However, no studies to date have evaluated the efficacy of AO administration to target peripheral vascular inflammation and dysfunction in patients with HFpEF.PurposeThe present study sought to evaluate the efficacy of an over‐the‐counter antioxidant (AO) cocktail (600mg alpha lipoic acid, 1,000mg vitamin C, and 600IU vitamin E) to acutely mitigate inflammation and oxidative stress, and subsequently improve vascular function, in patients with HFpEF.MethodsFlow mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit vessel and microvascular function, respectively, following administration of either placebo (PL) or AO in 16 HFpEF patients (73±10yrs) using a double‐blind, crossover design. Circulating biomarkers of inflammation (C‐reactive protein, CRP), oxidative stress (Malondialdehyde and Protein Carbonyl), free radical concentration (EPR Spectroscopy), antioxidant capacity, and nitric oxide (NO) bioavailability (plasma nitrate, NO3− and nitrite, NO2−) were also assessed.ResultsFMD improved following AO administration (PL: 3.49 ± 0.7%, AO: 5.83 ± 1.0%), while RH responses were similar between conditions (PL: 428 ± 51ml, AO: 425 ± 51ml). AO administration decreased CRP (PL: 4429 ± 705ng/ml, AO: 3664 ± 520ng/ml) and increased NO2− (PL: 182 ± 21nM, AO: 213 ± 24nM), but did not affect other biomarkers.ConclusionsThis study has identified the efficacy of an acute, over‐the‐counter dose of vitamins C, E, and alpha lipoic acid to mitigate vascular inflammation and improve conduit artery endothelium‐dependent vasodilation in patients with HFpEF, providing new insight into the mechanisms that govern peripheral vascular dysfunction in this patient group.Support or Funding InformationFunded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001311, RX001697, CX001183).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ablation of the Evolutionarily Acquired Functions of Atp1b4 Gene in Mice Increases Metabolic Capacity and Protects Against Diet‐Induced Obesity
Authors: Modyanov Nikolai 
Published: June 2021

Co‐option of vertebrate orthologous ATP1B4 genes in placental mammals radically changed properties of the encoded BetaM‐proteins. These proteins in lower vertebrates are authentic Na,K‐ATPase β‐subunits which in complex with catalytic α‐subunits function as ion pumps in the plasma membrane.In placental mammals BetaM proteins gained entirely different properties through structural changes of N‐terminal domains. As a result of these evolutionary alterations, eutherian BetaM completely lost its ancestral role and became the only currently known skeletal and atrial cardiac muscle‐specific protein of the inner nuclear membrane, which is expressed at highest level during perinatal development and is implicated in gene expression regulation.Loss of BetaM the Atp1b4 knockout mouse model results in significantly lower body size and weight, growth retardation and high mortality of neonates. Transcriptome analysis by mRNA sequencing of skeletal muscle from neonatal wild type and knockout littermates revealed broad changes in expression of genes regulating lipid metabolism. These results imply that BetaM plays an essential role during a critical period of perinatal and neonatal development of placental mammals and its damage or malfunction can cause birth and growth defects in humans.Most importantly, Atp1b4 disruption exhibits a somewhat unexpected and profound beneficial effect of on metabolic parameters in adult male mice. BetaM deficient (Atp1b4‐/Y) mice have significantly lower body weight and remarkably low adiposity. They exhibit lower fasting blood glucose, enhanced insulin sensitivity and improved glucose tolerance and are resistant to high‐fat diet‐induced obesity as compared to their wild type littermates. Knockout mice display higher heat production associated with increased food intake, elevated oxygen consumption especially in darkness and higher locomotor activity. Lower respiratory exchange ratio of knockout mice indicates that fat from high‐fat diet is metabolized rather than deposited as storage. These robust changes in mouse metabolic parameters induced by Atp1b4 disruption clearly demonstrate that eutherian BetaM plays the important role in development of pathways regulating metabolism of adult mice.The Atp1b4 ablation resulting in loss of evolutionarily acquired BetaM functions is in fact a simulation of the alternative pathway of mammalian evolution.Support or Funding InformationThis work was supported by Department of Physiology & Pharmacology and Center for Diabetes and Endocrine Research, University of Toledo College of Medicine.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Uncoupling Protein 3 Deficiency Impairs Contractile Recovery in a Rat Model of Myocardial Infarction and Reperfusion
Authors: Mahmoudi Elena , Lomax Tyler M. , Harmancey Romain 
Published: June 2021

Insulin resistance and diabetes are associated with poor prognosis following myocardial infarction and reperfusion (MI/R). Uncoupling protein 3 is a mitochondrial anion carrier which is down‐regulated by up to 50% in humans and animal models with obesity, insulin resistance, and type 2 diabetes. We previously reported that isolated hearts from Sprague Dawley rats which have been genetically modified to mimic this UCP3 deficiency (ucp3+/−) have poorer recovery of contractile function linked to an impairment of long‐chain fatty acid oxidation when subjected to ischemia/reperfusion. The goal of the present study was to extend these findings by investigating whether UCP3 deficiency similarly affects cardiac recovery in response to MI/R in vivo. Male ucp3+/− rats (n=16) and their wild type ucp3+/+ littermates (n=7) were subjected to 45 min MI by ligation of the left anterior coronary artery. Cardiac structure and function were assessed by echocardiography before surgery and at 2, 14, and 28 days following MI/R. On the 28th day, left ventricular (LV) hemodynamic parameters were measured with a Millar pressure‐volume catheter. Masson's trichrome staining was then performed to measure the infarct size relative to LV area. The mortality rate at 24 hrs post MI/R was higher in ucp3+/− rats (44%) when compared to the ucp3+/+ controls (28%). At day 28 post MI/R, LV ejection fraction (22.6±1.5 vs. 36.6±2.9%), fractional shortening (10.9±0.7 vs. 19.8±1.2%). and LV end‐systolic anterior wall thickness (LVAWs; 1.3±0.1 vs. 2.0±0.1 mm) were all significantly decreased for the ucp3+/− rats. Analysis of LV pressure‐volume loops also revealed greater impairment for −dP/dt min (1898+167 vs. 2832+380 mm Hg s−1), dP/dt max (1956±213 vs. 2981±219 mm Hg s−1), and for the LV relaxation time constant (Tau; 12.6±1.0 vs. 18.7±2.1 ms). The infarct size was also bigger for ucp3+/− rats (52±4 vs. 26±4%). In summary, the results demonstrate that partial UCP3 deficiency is sufficient to impair functional recovery of the heart following MI/R in vivo. Future studies will determine whether the defect can be corrected by implementing therapeutic strategies aiming to improve fatty acid oxidation at reperfusion.Support or Funding InformationThis work was supported by NIH Grants R01HL136438, R00HL112952, P01HL051971, and P20GM104357.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial to Mesenchymal Transition in the Rat Heart Following Exposure to a Model of Posttraumatic Stress Disorder
Authors: Rorabaugh Boyd R. , Mabe Nathaniel W. , Stoops Thorne S. , Seeley Sarah L. , Mulcher Kasey E. , Ney Connor P. , Goodman Cassandra S. , Hertenstein Brooke J. , Rush Austen E. , Kasler Charis D. , Sargeant Aaron M. , Zoladz Phillip R. 
Published: June 2021

People who are exposed to life‐threatening trauma are at risk of developing posttraumatic stress disorder (PTSD). In addition to psychological manifestations, PTSD is associated with increased risk of myocardial infarction and arrhythmias. We previously reported that rats exposed to a predator‐based model of PTSD develop myocardial hypersensitivity to ischemic injury. The present work provided mechanistic insight into changes in cardiac gene expression and histology that may predispose the heart to injury induced by an ischemic insult. Male rats were subjected to two cat exposures (separated by a period of 10 days) and daily cage‐mate changes for 31 days. Control rats were not exposed to the cat or cage‐mate changes. Ventricular tissue was analyzed by RNA sequencing, western blotting, histology, and immunohistochemistry. Gene expression analysis identified clusters of upregulated genes associated with endothelial to mesenchymal transition in hearts from stressed rats. This was supported by upregulation of α‐smooth muscle actin and a decrease in the number of CD31 positive endothelial cells. Multifocal lesions characterized by necrosis, mononuclear cell infiltration, and collagen deposition were observed in hearts from all stressed rats but not in any of the control rats. These changes in gene expression and phenotype are indicative of endothelial to mesenchymal transition and may underlie the myocardial hypersensitivity to ischemic injury that develops in these animals. Similar changes in the human heart may also underlie the increased frequency of myocardial infarction, arrhythmias, and other cardiac abnormalities in humans with PTSD.Support or Funding InformationThis work was supported by grant R15HL132322 awarded to BRR.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The therapeutic relevance of the cardiovascular response to stroke in treated and untreated Spontaneously Hypertensive Rats (SHR)
Authors: Thakkar Pratik C , Barrett Carolyn Judith , Guild Sarah‐Jane Judith , McGregor Ailsa , Paton Julian Judith , McBryde Fiona Dianne 
Published: June 2021

Over 80% of patients manifest a transient rise in blood pressure (BP) after ischemic stroke, regardless of their previous blood pressure level. In the spontaneously hypertensive rat (SHR), we investigate the cardiovascular response to stroke in animals already receiving chronic anti‐hypertensive treatment and evaluate the impact of actively controlling BP after stroke in these animals.Male SH rats (n=16, 374±5 g) were instrumented to allow the long‐term recording of BP and brain tissue oxygen in the penumbra (pO2) via telemetry. Resting BP was controlled for four weeks using the angiotensin‐converting enzyme inhibitor enalapril (10mg/kg/day in drinking water). After recording a 3‐day baseline, on D0, an ischemic stroke was induced via a two‐hour transient occlusion of the middle cerebral artery (MCAo). After a stroke, treatment with enalapril was continued in all rats (10mg/kg/day sc via osmotic pump) either alone (Untreated, n=8) or in conjunction with the clinically‐indicated adrenergic antagonist, labetalol (0.25mg/kg/hr sc via osmotic pump) to prevent post‐stroke hypertension (Treated n=8). Behavioural testing and neurological scoring (SHIRPA score) were performed on Days 1, 3, 7 and 10 to evaluate the functional recovery over time, and post‐mortem stroke infarct size was assessed by histology on D10.Enalapril treatment significantly and consistently reduced baseline BP to a normotensive level (from 142±1 to 116±3 mmHg, p<0.001). Following a stroke, BP increased rapidly in the Untreated rats, reaching a peak of 14±3 mmHg above baseline on Days 0 and 1 (p<0.05). Post‐stroke hypertension was successfully prevented in the Treated group, with BP significantly lower than in Untreated rats (p<0.05). Penumbra tissue oxygen levels were increased significantly above baseline in Treated animals on D1 and D2 (p<0.05), consistent with previous reports that labetalol preserves or increases cerebral blood flow despite lowering BP. Untreated and Treated rats showed a similar pattern of functional impairment and recovery after stroke, however, the infarct volume was significantly smaller in Treated animals on D10 (276±8mm3 vs Treated 220±16mm3, p<0.05).We show that a pronounced increase in BP occurs after stroke in controlled hypertensive animals. We hypothesized that this post‐stroke hypertension may be a protective response, aiding perfusion of the ischemic penumbra. Our results showed that preventing post‐stroke hypertension did not appear to have a negative impact on the functional recovery from stroke and that labetalol treatment may in fact enhance cerebral blood flow.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Amelioration of Nω‐Nitro‐L‐Arginine Methyl Ester (L‐NAME)‐induced hypertension and cardio‐renal oxidative stress by the methanol bark extract of Persea americana
Authors: Omobowale Temidayo , Adejumobi Olumuyiwa , Oyagbemi Ademola , Ogunpolu Blessing , Adedokun Rahamon , Adedapo Adeolu , Yakubu Momoh 
Published: June 2021

Hypertension is a leading cause of cardiovascular morbidity and mortality. Uncontrolled hypertension causes end organ damage resulting in hypertensive cardiomyopathy and nephropathy. Traditionally, P. americana bark extract (PABE) is commonly used as a remedy for hypertension in Nigeria. In this study, we investigated the probable ameliorative effects of PABE on L‐NAME induced hypertension and cardiorenal oxidative stress.Sixty (60) male Wistar albino rats were grouped into six groups each containing 10 rats. Group A, the control, was administered potable water. Groups B‐F received orally, 40 mg/kg of L‐NAME only, 40 mg/kg of L‐NAME+100 mg/kg of PABE extract, 40 mg/kg of L‐NAME+200 mg/kg of PABE extract, 40 mg/kg of L‐NAME+400 mg/kg of PABE extract and 40 mg/kg of L‐NAME+ 0.25 mg/kg of lisinopril, respectively for 21 daysL‐NAME administration caused a significant (p <0.05) increase in systolic, diastolic and mean arterial blood pressure as well as markers of oxidative stress namely H2O2, Malondialdehyde, Protein carbonyl and AOPP in cardiac and renal tissues. Immunohistochemistry showed increased expressions of CTn1, NRF2 and NFkB in the cardiac tissues and also KIM‐1, NRF2 and NFkB in the kidney tissues of the group treated with L‐NAME alone compared to the control.Treatment with PABE caused a significant (P<0.05) decrease in blood pressure, an improvement in antioxidant defense systems, reduction in markers of oxidative stress, cardiac and renal injury and inflammation comparable with that of lisinopril.The results obtained from this study suggest the ameliorative effect of PABE on L‐NAME‐induced hypertension and cardiorenal oxidative stress and hence, its potential as an antihypertensive supplement.Support or Funding InformationTertiary Education Trust Fund (TETFUND), NigeriaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.