bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Intimal Alteration of Human Varicose Veins Is Associated with Oxidative Stress and Cyclooxygenase‐2 Dependent Mechanisms
Authors: Velasco‐Martin Juan , Aguado Andrea , Mendez Iago , España‐Caparros Gabriel , Salaices Mercedes , Regadera Javier , Briones Ana 
Published: June 2021

Chronic venous insufficiency (CVI) determinates high morbidity. Main varicose histological lesions include intimal fibrosis, luminal dilation and progressive vascular wall thickening. Plasma biomarkers of oxidative stress are increased in CVI patients. We evaluated histological changes and local inflammatory profile, particularly oxidative stress and prostanoids, in varicose saphenous veins (SV).10 distal and proximal segments of SV from patients with CVI were studied. In intimal layer, expression of smooth muscle actin (SMA), collagen I/III, and elastic fibers distribution were quantified by ImageJ sofware. NADPH oxidase subunit 4 (NOX‐4), cyclooxygenase‐2 (COX‐2), microsomal prostaglandin E synthase (mPGES‐1),MAC3, SMA, elastin, collagen I/III were studied by RT‐PCR. H2O2 production and NADPH oxidase activity were evaluated by commercial kits.Histological analysis showed higher intimal expression of SMA, collagen I/III and elastic fibers in proximal segments compared to distal segments. The progressive intimal vein thickness is inversely related to the ratio of SMA, collagen I/III and elastic fibers respect to intimal area. mRNA expression of SMA, collagen I/III, elastin, NOX‐4 and COX‐2 but not of mPGES‐1 or MAC3, H2O2 production and NADPH oxidase activity are upregulated at proximal varicose segments compared to distal segments. Our results suggest that oxidative stress and COX‐2 derived prostanoids might be implicated in the initial stages of the intimal fibrosis observed in varicose SV. Supported by PI13/01488 and SAF2012‐36400.
Selective Antagonism of mGlu5 Alters Sleep‐wake and Spectral EEG and Ameliorates Behavioral Abnormalities in a Rodent Model of Traumatic Stress
Authors: Nedelcovych Michael , Gould Robert , Gong Xuewen , Felts Andrew , Grannan Michael , Thompson Analisa , Ivarsson Magnus , Emmitte Kyle , Lindsley Craig , Conn Jeffrey , Jones Carrie 
Published: June 2021

Traumatic stress induces state‐dependent alterations in cortical network activity as measured by sleep‐wake and quantitative electroencephalography (qEEG) that may predict the onset or severity of chronic post‐traumatic stress disorder (PTSD) symptoms. Activation of metabotropic glutamate receptor 5 (mGlu5) promotes fear memory consolidation, and may contribute to sleep disturbances after trauma. The single prolonged stress (SPS) rodent model of traumatic stress recapitulates many physiological and behavioral correlates of the human disorder, but its effect on sleep‐wake and qEEG spectral power has not been examined.Male Sprague‐Dawley rats were implanted with telemetric EEG electrodes continuously recording cortical activity before and after SPS. VU0409106, a selective mGlu5 negative allosteric modulator (NAM) was administered after SPS to assess blockade or reversal of SPS‐induced sleep‐wake and qEEG disturbances.SPS caused persistent PTSD‐like alterations in rapid eye movement (REM) sleep and non‐REM (NREM) sleep as well as changes in state‐dependent spectral power, such as an increase in waking beta (18‐30Hz) power, and a decrease in NREM delta (0.5‐4Hz) power indicative of hyperarousal and poor sleep quality. VU0409106 modulated SPS‐induced sleep‐wake architecture changes and qEEG spectral power alterations and ameliorated accompanying anxiety‐like behaviors.
Emerging role of epigenetic in pulmonary arterial hypertension right ventricular failure
Authors: Potus Francois , Ruffenach Gregoire , Provencher Steeve , Bonnet Sébastien 
Published: June 2021

INTRODUCTIONPulmonary arterial hypertension (PAH) is associated with a global impairment of angiogenesis. Although the origin of the angiogenic defect remains unknown. since a few years epigenetic has become an important research area in many diseases including PAH. Role for miRNAs has been widely demonstrated; nonetheless a role for long noncoding RNA (LncRNA) remains unknown. In the present study we focused our role on the expression level of miR‐126 and MALAT‐1 both of which are enriched in endothelial cells and known to be implicated in angiogenesis regulation. We hypothesized that aberrantly express miR‐126 and MALAT‐1 contributes to angiogenesis impairment see in PAH.RESULTSUsing qRT‐PCR we showed that miR126 was decreased in human PAH RV (p<0.05) compare to control while MALAT‐1 expression was upregulated p<0.05). These finding were associated in vitro with a significant reduction in EC proliferation (Ki67;p<0.05) and tube formation (p<0.05) measured in freshly isolated human RV endothelial cells from both PAH compare to EC from control RV. Both miR‐126 and MALAT‐1 are critical regulators of angiogenesis and are likely dependent of each other; in fact we showed that miR‐126 expression inversely correlates with MALAT‐1 expression in PAH RV (p<0.05). CONCLUSIONWe demonstrated, for the first time in PAH that the endothelial‐enriched noncoding RNAs miR‐126 and MALAT‐1 are aberrantly expressed in human RV from PAH patients contributing to the impairment of angiogenesis. The endothelial specific miR‐126 is known to regulate endothelial cells proliferation while MALAT‐1 up regulation has been associated with decreased endothelial cells migration and sprouting, suggesting that these two noncoding RNAs are implicated in angiogenesis defect.
β‐amyloid Peptide‐Induced Human Arteriole Endothelial Dysfunction is Attenuated by Nanoliposomes
Authors: Guzman‐Villanueva Diana , Madine Jill , Truran Seth , Davies Hannah , Burciu Camelia , Franco Daniel , Weissig Volkmar , Migrino Raymond 
Published: June 2021

Microvascular impairment is an under‐recognized pathologic mechanism of misfolded protein diseases and is critical in early Alzheimer's disease (AD). We showed that β‐amyloid 42 (Aβ), a peptide involved in AD, induces endothelial dysfunction in human adipose/leptomeningeal arterioles. Nanoliposomes (NL) are phospholipid containing particles that altered the structural properties of another amyloid protein (AL amyloid light chains) and restored endothelial function.AimTo determine if phosphatidic acid (PA) containing NL (NLPA) prevent Aβ fibril formation and restore endothelial function in human arterioles exposed to Aβ.MethodsNLPA (70% cholesterol, 25% phosphatidylcholine, 5% PA) were mixed with Aβ and fibrillation rate measured by thioflavin T fluorescence. Human abdominal subcutaneous adipose arterioles were isolated and constricted with endothelin‐1. Baseline control dilation was measured following acetylcholine (10‐9‐10‐4M) and papaverine (10‐4M); after washing arterioles were exposed to 2 µM Aβ±NLPA (1:10 mass) and dilator response was measured. Human umbilical vein endothelial cells (HUVEC) were exposed to Aβ±NLPA (24 hrs) and nitric oxide (NO) gas was measured.ResultsNLPA prevented Aβ fibril formation (F1). Aβ induced impaired dilator response to acetylcholine and papaverine while reducing HUVEC NO (F2). These changes were attenuated by NLPA.ConclusionsNL prevent Aβ amyloid fibril formation. NL reduce Aβ‐induced endothelial and non‐endothelial arteriole dysfunction, the former likely by increasing NO. Nanoliposomes represent a novel treatment approach to amyloid protein diseases such as AD.
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Effect of Ultrasonic Bone Stimulation of the Mastoid on Renal and Coronary Blood Flow in Humans
Authors: Ray Chester , Park Susie , Sauder Charity 
Published: June 2021

We have previously demonstrated that external stimulation of the otolith organs by ultrasonic bone stimulation (UBS) of the mastoid increases muscle sympathetic nerve activity. These responses are similar to that observed by head‐down rotation. Additionally, stimulation of the vestibulosympathetic reflex by head‐down rotation elicits leg and renal vasoconstriction. The purpose of this study was to determine if UBS elicits vascular changes to the renal and coronary arteries. We hypothesized that UBS would elicit vasoconstriction in the renal but not the coronary vascular bed. Ten subjects (3 F, 7 M; 25±1 yr; 174.0±3.2 cm; 71.8±4.3 kg) performed UBS in the supine position for 3 min during measurement of arterial blood pressure, heart rate, renal blood flow, and coronary blood flow. Blood flow was measured using Doppler ultrasound. UBS did not change mean arterial blood pressure (Δ‐1±1 mmHg) or heart rate (Δ‐1±1 beats/min) from baseline. Renal vascular conductance was significantly decreased from baseline during UBS (0.63±0.03 and 0.60±0.04 cm/s/mmHg, respectively; P=0.02). However, there were no changes in coronary vascular conductance during UBS (0.18±0.01 and 0.18±0.02, for baseline and UBS, respectively). In conclusion, UBS can elicit vasoconstriction of the renal vascular bed similar to that observed during head‐down rotation. This finding suggests that external stimulation of the otolith organs might assist in postural blood pressure regulation in people with decreased orthostatic tolerance.Supported by: NIH R21HL109952
MK2 Phosphorylates Capase 3 and Regulates Nuclear Translocation of Cleaved Caspase 3 during LPS mediated Apoptosis
Authors: Damarla Mahnendra , Johnston laura , Kim Bo , Kolb Todd , Damico Rachel , Merchant Michael , Rane Madhavi , Machamer Carolyn , Hassoun Paul 
Published: June 2021

BackgroundApoptosis is a necessary event in the development of acute lung injury (ALI). Recent reports have identified nuclear translocation of active caspase 3 is necessary for the execution of apoptosis. The molecular mechanism(s) by which cleaved caspase 3 translocates to the nucleus are not well understood.MethodsWild Type and MK2‐/‐ mice were exposed to intravenous (IV) lipopolysaccharide (LPS), after which lungs were harvested for tissue analyses. Kinase activity assays using MK2 and caspase 3 were also performed.ResultsIn response to IV LPS, WT mice exhibited a significant increase in apoptosis accompanied by increases in markers of lung injury. However, MK2‐/‐ mice were protected from both apoptosis and lung injury. Interestingly, cleaved caspase 3 translocated to the nucleus in WT mice while it was sequestered in the cytosol in MK2‐/‐ mice. 2‐D gel analyses of caspase 3 in lung lysates from LPS exposed WT mice demonstrated a shift toward the positive electrode on an isoelectric gradient. This shift was lost with phosphatase pretreatment; appearing identical to lysates from MK2‐/‐ mice exposed to LPS. Furthermore, protein kinase assays confirmed that MK2 directly phosphorylates caspase 3 and mass spectrometry analysis identified two potential phosphorylation sites.ConclusionTaken together, our results suggest that caspase 3 is a potential substrate of MK2 and, once modified (i.e. phosphorylated), undergoes differential processing, which may account for the differential localization once cleaved in MK2 deficient states.
Activation of Anoctamin‐1 Causes Apoptosis of Pulmonary Vascular Endothelial Cells
Authors: Allawzi Ayed , Vang Alexander , Choudhary Gaurav 
Published: June 2021

BackgroundWe have shown that Anoctamin‐1 (Ano1) is expressed in pulmonary endothelial cells (ECs) and causes EC hyperpolarization. However, the functional role of Ano1 in pulmonary vascular ECs is unknown. We sought to elucidate the role of Ano1 in EC proliferation.MethodsChanges in Ca2+ levels were assessed using Fluo‐4 AM. Changes in ECs cell numbers were performed by haemocytometer counts. p38 phosphorylation was probed using immunoblot. Cell cycle and apoptosis was assessed using flow cytometry and PI or Annexin V/PI staining respectively.ResultsActivating Ano1 resulted in a significant change in Ca2+, however there was some heterogeneity with some cells exhibiting marked increases in Ca2+. Cell counts revealed that activation of Ano1 significantly decreased cell number, that was attenuated in presence of chloride channel inhibitors, DIDS and T16Ainh‐A01. Ano1 activation did not alter cell cycle progression but increased p38 phosphorylation, and preliminary data suggest increased apoptosis.ConclusionAno1 is expressed in the pulmonary endothelium and activation leads to a decrease in cell number, likely mediated via apoptosis.
Decreased PGC‐1α‐SIRT1 Signaling Leads to Impaired Angiogenesis in Persistent Pulmonary Hypertension of the Newborn (PPHN)
Authors: Konduri Girija , Callan Emily , Afolayan Adeleye , Teng Ru‐Jeng 
Published: June 2021

IntroductionPPHN is characterized by increased pulmonary vascular resistance (PVR) at birth resulting in hypoxemia. Impaired angiogenesis contributes to high PVR in PPHN. Pulmonary artery endothelial cells (PAEC) in PPHN show decreased mitochondrial respiration, increased apoptosis and impaired angiogenesis. Objective: Investigate the hypothesis that down‐regulation of Peroxisome Proliferator‐Activated Receptor Gamma Co‐Activator‐1α (PGC‐1α) and histone deacetylase, Sirtuin‐1 (SIRT‐1) lead to impaired mitochondrial biogenesis and angiogenesis in PPHN. Methods: PAEC were isolated from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction from 80% to term gestation and matched controls. PGC‐1α and SIRT‐1 levels were evaluated by immunoblotting. PGC‐1α was knocked down in control PAEC and overexpressed in PPHN PAEC to investigate effects on mitochondrial complex proteins I‐V and angiogenesis. Angiogenesis was assessed in vitro by tube formation, cell migration and proliferation. Results: PPHN PAEC had significant decreases in PGC‐1α and SIRT‐1 levels vs. controls (p<0.01). PGC‐1α knockdown in control PAEC lead to decreased tube formation (p<0.0001), cell migration (p<0.01) and proliferation (p<0.0001). PGC‐1α over‐expression in PPHN PAEC lead to significant increases in mitochondrial ETC proteins‐ complex I (p<0.0001), II (p=0.0433), III (p=0.0384), and V (p=0.0462), as well as increased tube formation (p<0.0001), cell migration (p<0.01) and proliferation (p<0.0001).ConclusionCoordinated downregulation of PGC‐1α and SIRT1 contribute to decreased mitochondrial biogenesis and angiogenesis in PPHN. This mechanism offers a new therapeutic target in PPHN.
Characterizing Renal Dysfunction in the Face of Hypertension and Heart Failure
Authors: Brooks Steven , Frisbee Jefferson , Chantler Paul , Olfert Mark , Brock Robert 
Published: June 2021

Recent work highlights how small decrements in renal function, even those that are transient, have significant negative prognostic effects on outcomes in patients with heart failure. Yet, it is unclear if heart failure secondarily leads to diminished renal function or if mild renal dysfunction leads to progression of functional cardiac deterioration.To better understand the association between the concomitant development of renal dysfunction and heart failure, a comprehensive assessment of renal function in the male spontaneously hypertensive, heart failure‐prone rat (SHHF) was performed. Various biomarkers of renal function were evaluated. At 37‐40 weeks, severe hypertension (MAP greater than 170) was measured in all SHHF rats. Serum albumin content in the SHHF was significantly diminished throughout the experimental period, indicating the possibility of renal dysfunction. Although the ratio of serum urea to creatinine increased significantly in SHHF, creatinine levels remained normal, suggesting that renal filtration is likely not compromised and that the increase is a reflection of inadequate blood flow. To corroborate this possibility further, cortical peritubular capillary networks were imaged using intravital microscopy and showed that renal microvascular blood flow in SHHF was, in fact, diminished.Together, these data confirm that renal dysfunction occurs in the setting of hypertension and heart failure, and is an early manifestation of blood flow deficits. We now offer an alternative pathway to the conventional thinking of the cardiorenal axis that should serve as a stimulus for developing novel therapeutic interventions for heart failure.
Truncated Variant of ASIC2b Confers Epithelial Sodium Channel Properties to ASIC2: Role in Nephrotic Syndrome
Authors: Doucet Alain , Sassi Ali , Brideau Gaelle , Cheval Lydie , Vogt Bruno , Fila Marc 
Published: June 2021

Sodium retention responsible for nephrotic edema stems from epithelial sodium channel (ENaC) and Na,K‐ATPase induction in cortical collecting ducts (CCD) of puromycin aminonucleoside (PAN) nephrotic rats. However PAN rats show hyper‐aldosteronemia whereas most nephrotic patients do not. Aldosterone‐clamped (AC) PAN rats still retain sodium in ASDN although ENaC is no longer expressed. We searched for an alternate sodium entry pathway in CCD from AC‐PAN rats, a more relevant model of human disease.By RACE we isolated from AC‐PAN rat kidney a cDNA identical to that of ASIC2b except that it lacks the 207 3′‐most nucleotides. This truncated sequence contains an ATG within the reading frame of the full length sequence. Heterologous expression in OKP cells demonstrated that it is translated in a protein lacking the 71 N‐ter amino acids. Two‐electrode voltage clamp analysis in Xenopus ovocytes showed that co‐expression of truncated ASIC2b and ASIC2a induces an acid‐stimulated cation current which, instead of being transient, lasts as long as the stimulus is maintained. ASIC2a and truncated‐ASIC2b thus constitute heteromeric channels potentially supporting epithelial sodium transport. ASIC2b expression is induced in CCD of AC‐PAN rats where it localizes at the apical pole. ASIC2b was detected in kidney biopsies from 5/8 patients with idiopathic nephrotic syndrome but not in 26/26 patients with other renal diseases. In ASIC2b‐positive nephrotic patients, ASIC2b was located in CCD.Results suggest that truncated ASIC2b/ASIC2a mediates sodium retention in nephrotic syndrome and appears as a new therapeutic target.
Sirtuins as negative regulators of cardiac fibrosis
Authors: Samant Sadhana , Bindu Samik , Ghorpade Prabhakar , Pillai Vinodkumar , Gupta Mahesh 
Published: June 2021

Background and ObjectiveFibrosis results from a process where quiescent resident fibroblasts in a healthy tissue get transformed into myofibroblasts (myoFB). In the US an estimated 45% deaths per year are attributed to fibrotic diseases. Tissue fibrosis is considered one of the causative factors of the aging process and organ dysfunction. Sirtuins, the NAD+‐dependent deacetylases are shown to impact lifespan of organisms. Among the seven sirtuin isoforms expressed in mammalian cells, SIRT6 and SIRT3, which are localized in the nucleus and mitochondria, respectively, are shown to retard the aging‐associated diseases. We therefore set out to study their roles in development of tissue fibrosis.Methods and ResultsFibroblasts isolated from human failing hearts showed increased expression of myoFB markers, including expression of α‐smooth muscle actin, fibronectin and collagen1 with concomitant decreased levels of SIRT6 and SIRT3. By immunoblotting and Masson‐trichrome staining we also observed up‐regulation of these myoFB markers in SIRT6(+/‐) and 12‐month old SIRT3(‐/‐) hearts, compared to age‐matched littermates,. These hearts also showed up‐regulation of TGF‐β1 and Smad3 levels. In experiments where SIRT3 or SIRT6 knocked‐down human cardiac fibroblasts were challenged with the pro‐fibrotic agonist angiotensin‐II, we observed significantly higher levels of TGF‐β1 and myoFB markers, compared to control fibroblasts. Over‐expression of these sirtuin isoforms reverted back the myoFB phenotype.ConclusionThough, SIRT6 and SIRT3 are localized in two different cellular compartments, both are capable of restraining TGF‐β signaling and blocking transformation of fibroblasts into myoFB. These sirtuins therefore can be considered candidates for designing anti‐fibrotic drugs. .
Blood Pressure Responses to Isometric Handgrip in Women With and Without a History of Hypertensive Pregnancy
Authors: Ranadive Sushant , Harvey Ronee , Miller Virginia , Joyner Michael , Barnes Jill 
Published: June 2021

Hypertensive pregnancy (HP) is considered a risk factor for cardiovascular disease. Blood pressure (BP) response to physical stressor is an independent marker of cardiovascular risk. However, there is limited data regarding the pressor response to acute physical stress in women with a history of HP. Hence, the aim of the study was to compare BP responses in women with a history of HP to age and parity matched controls.Beat to beat BP was recorded in postmenopausal women (age = 59 ± 1 yrs, BMI = 31 ± 2 kg/m2) with and without a history of HP at baseline and during isometric handgrip (HG) exercise (30% of MVC) to fatigue. Isometric handgrip exercise was followed by 90 seconds of supra‐systolic cuff occlusion on the exercising arm.In both groups combined (N=31), systolic blood pressure (SBP) increased significantly from baseline to HG to cuff inflation (143 ± 3 to 161 ± 3 to 167 ± 4 mmHg). Similarly, mean arterial pressure (MAP) increased significantly from baseline to HG to cuff inflation (106 ± 2 to 119 ± 2 to 122 ± 2 mmHg). Diastolic pressure (DBP) increased significantly only from baseline to HG (80 ± 1 to 88 ± 1 mmHg) and baseline to cuff inflation (89 ± 2 mmHg). However, there were no significant differences in SBP, DBP and MAP between women with and without a history of HP (p>0.05).Even though both groups had an increase in BP variables in response to HG and cuff occlusion, there was no difference in the BP response to acute physical stressors in women with a history of HP as compared to control participants.Funding: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154 (JNB)
Correlation of Body Mass Index and Cardiovascular Reactivity to Exercise Induced Stress in Young Adults.
Authors: Mohesh Glad , Prasath Ajith , Palanisamy Poornima , Vijayakumar Abinaya , A Sundaramurthy 
Published: June 2021

Cardiovascular reactivity (CVR) is an increase in heart rate and blood pressure when exposed to stress. Increased CVR to stress is an indicator of developing hypertension. In this study we have tried to understand if exaggerated CVR and obesity are related to each other.MethodsInstitutional Ethics Committee (Human Studies) clearance was obtained and a convenient sampling of 32 females and 32 males were done based on their age(>18 to <25years), and normotensive status. Baseline blood pressure, heart rate and five minutes finger photoplethysmography was recorded. Pulse wave contour analysis gave the pulse transit time, stiffness index and reflection index. A pedometer was hooked to the waistband of the subject and was asked to walk around the department corridor with an average speed of 100 steps in 1 minute to count 3000 steps in 30 minutes. After 3000 steps, immediate measurement of heart rate, blood pressure, and finger plethysmography for 5minutes was done in supine lying position. Pearson's correlation method and paired t test was done with statistical significance set at p<0.05.ResultsA positive correlation existed between the BMI and various reactivity measures of the heart rate, systolic blood pressure and diastolic blood pressure .A definite trend of positive correlation was noticed
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imageThere was an inverse relationship between the BMI and elasticity of the arteries.ConclusionAutonomic nervous system is the most powerful energy saving regulatory system in our body. Failure of this system will lead to deposition of fat in one's body leading to Obesity. Reduced autonomic activity in obese subjects is a risk factor for cardiovascular morbidity.