bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiopoietin like‐2 stimulates leukocytes adhesion to the native aortic endothelium in LDLr−/−; hApoB100+/+ mice
Authors: Farhat Nada , Thorin-Trescases Nathalie , Villeneuve Louis , Allen Bruce G. , Thorin Eric 
Published: June 2021

Angiopoietin like‐2 (Angptl2), which circulating levels are increased in patients with coronary artery disease, could contribute to chronic inflammation. We hypothesized that the pro‐inflammatory effect of Angptl2 contributes to atherogenesis by stimulating leukocyte adhesion in atherosclerotic mice (LDLr−/−; hApoB100 +/+, ATX).In C57Bl/6 control mice (WT), Angptl2 levels increased with age (P<0.05) in the plasma and the aorta. In ATX mice, levels were higher (P<0.05) than in WT mice both in plasma (3 folds) and the aorta (2 folds), and they further rose with age (P<0.05). In vitro, basal endothelial levels of TNF‐α and IL‐6 gene expression were higher in ATX compared to WT mice; stimulation with Angptl2 (100 nM) further raised their expression in both WT and ATX mice. Ex vivo, Angptl2 stimulated the adhesion of leukocytes on the native endothelium of the aorta of ATX mice (P<0.05), but not WT mice. Leukocytes adhesion on the endothelium was due to a rise (P<0.05) in the abundance of adhesion molecules (mRNA and protein) and the surface of endothelial cells (ICAM‐1) and leukocytes (Mac‐1, L‐selectin and PSGL‐1). Antibodies against P‐selectin or ICAM‐1 prevented (P<0.05) leukocyte adhesion in ATX mice.Our data suggest that Angptl2 could significantly contribute to the atherosclerotic process by stimulating pro‐inflammatory cytokines secretion and leukocytes adhesion.
Nasal Spray of Bioactive Polyphenol Metabolites as a Novel Therapy for Alzheimer's Disease and Other Forms of Dementia
Authors: Knable Lindsay Alexis , Wang Jun , Ferruzzi Mario G , Vempati Prashant , Freire Daniele , Gong Bing , Pasinetti Giulio Maria 
Published: June 2021

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity and limited knowledge regarding their bioavailability, metabolism and bioactivity in the brain. We recently demonstrated that dietary supplementation with a grape‐derived polyphenolic preparation, namely a monomeric‐enriched catechin and epicatechin fraction (Mo), significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). We also found that Mo treatment resulted in the accumulation of proanthocyanidin metabolites in the brain at a concentration of ~400 nM. One of the metabolites identified in the brain following Mo treatment, Metaphenol‐A1, was shown to promote basal synaptic transmission and long term potentiation (LTP) at physiologically relevant concentrations in hippocampal slices through mechanisms associated with cAMP‐response‐element‐binding‐protein signaling. In this study, we tested whether application of Metaphenol‐A1 via a novel, non‐invasive intranasal delivery apparatus can effectively improve LTP and cognitive function in the AD mice. Our study will provide insights into developing a novel, safe approach to directly deliver a bioactive therapeutic agent to the central nervous system for AD prevention/treatment.Supported by Discretional Funds to GMP.
Viability of two sub‐strains of C57BL/6 mice in response to cardiac pressure‐overload
Authors: Parikh Jay , Wang Sophia , Azizi Khalid , Bird Elizabeth , Spellman Matthew , Lai N. Chin 
Published: June 2021

The inbred mouse strain C57BL/6 is highly suitable and commonly used for the generation of transgenic mice as tools in dissecting biological processes and diseases. However, this parent line is available from a variety of sources with different sub‐strains. We examined male C57BL/6J mice from the Jackson Laboratory (n=29) and male C57BL/6NHsd from the Harlan Laboratories (n=36) in the setting of transverse aortic constriction (TAC), which is a common interventional procedure for studying pressure‐overload in hearts. Under anesthesia, the aortic arch between the innominate and the left carotid artery was constricted to 0.413 mm (27 ga needle) with a 7‐0 silk suture. Survival was monitored for 3 wks, and subsequently left ventricular function was assessed with a 1.4F Millar pressure transducer. Three wks after TAC, the survival rate was 50% for the C57BL/6NHsd and 79% survived for the C57BL/6J (Top Figure). A significant decline of 1058 mmHg/s (21%) in cardiac contractility (Bottom Figure) and 1228 mmHg/s (22%) in the rate of decay was found in C57BL/NHsd mice.ConclusionThis study demonstrates phenotypic differences in viability and cardiac performance in response to TAC for these two sub‐strains. Therefore, it is imperative to carefully consider the appropriate line for the design of transgenic mice.
Hypoxia attenuates the ability of cyclic guanine‐dependent protein kinase (PKG) to increase BK channel activity
Authors: Thorpe Richard Burdette , Williams James M , Pearce William Julian 
Published: June 2021

OBJECTIVEChronic hypoxia attenuates endothelium‐dependent vasodilatation, more in fetal than adult arteries. Here we examine the hypothesis that these effects involve inhibition of PKG activity and reduced BK channel activity.METHODSPregnant and Non‐Pregnant ewes were held at sea level (normoxic) or at 3820m (hypoxic) for the final 110 days of gestation. Carotid arteries from non‐pregnant adults and term fetal sheep were prepared for 5HT concentration‐response determinations with ±8‐pCPT‐cGMP and ±iberiotoxin. Abundances of α/β isoforms of PKG‐I were determined by Western blot. PKG activity was determined by enzyme assay.RESULTSPKG activation depressed 5HT‐induced contractility in normoxic but not hypoxic arteries. Hypoxia did not alter PKG abundance or specific activity but reduced iberiotoxin's ability to block PKG's effect on 5HT‐induced contractions, more in fetal than adult arteries.CONCLUSIONActivation of BK channels accounts for a significant portion of PKG‐induced vasorelaxation in ovine carotid arteries. Chronic hypoxia attenuates the ability of PKG to activate BK channels without effects on PKG activity or abundance.Supported by PHS Grants P01‐HD31226 and R01‐HL64867.
Stimulation of thromboxane A2 receptor induced the constriction and remodeling of the ductus arteriosus in the rat
Authors: Yokota Tomohiro , Aida Takashi , Shiraishi Ryosuke , Ichikawa Yasuhiro , Fujita Takayuki , Yokoyama Utako 
Published: June 2021

The ductus arteriosus (DA) is an essential vascular shunt that connects the pulmonary artery to the aorta in the fetus. After birth, the DA immediately closes. DA closure is occurred by its constriction and remodeling. Patency of the DA (PDA) is a common life‐threatening complication of premature infants. Although cyclooxygenase inhibitors are frequently used for PDA, they often show little effect with severe side‐effects. Thromboxane A2 receptor (TP) is related to the vasoconstriction and the proliferation and migration of vascular smooth muscle cells (SMC) in the atherosclerosis. Hence, we hypothesized that TP stimulation induced closure of the DA by inducing the constriction and remodeling.To assess the constrictive effect of the TP agonist U46619 on the DA, adjunct arteries, and peripheral vessels in vivo, we injected U46619 into the rat neonates and two distinct PDA models we generated. We found that U46619 induced DA constriction without constriction of other arteries in vivo. In addition, U46619 didn't form thrombosis in the lung. To investigate the role of TP stimulation in the DA remodeling, we examined the U46619‐induced intimal thickening (IT), proliferation, and migration using DA explant and cultured DA SMC. We found that U46619 induced IT by promoting the proliferation and migration of SMC. We conclude that TP agonists could be an alternative therapy for PDA.
The genetic association of polymorphisms rs599839, rs646776 and rs4970834, in chromosomal locus 1p13.3 with coronary artery disease
Authors: Rizk Nasser , El-Menyar Ayman , Wais Idil Souleman , Egue Huda , Baluli Hissa Mohamed , Al Suwaidi Jassim 
Published: June 2021

BackgroundAbnormalities in lipids with increased serum concentration of LDL‐C are risk factors for coronary artery disease (CAD), and atherosclerosis. The aim of this study was to investigate the association between serum LDL‐cholesterol, and significant coronary artery stenosis with well‐known genetic variants in chromosomal locus 1p13.3 among CAD patients with and without significant coronary artery stenosis [case and control groups] respectively.MethodsBlood was drawn from a total of 178 patients. Genotyping for the variants rs599839, rs646776 and rs4970834, were performed by the 5’ nuclease test using TaqMan assay.ResultsThe HDL‐C level of rs599839 was [12.01± 3.9 mM vs. 3.46± 1.45 mM] for GG vs. AA+AG using the recessive genetic model with p value=0.006. Using the additive model, rs64776 variant had a significantly higher triglycerides levels [7.76±2.25 vs. 1.74±0.15 mM] for AA vs. GG respectively with p value=0.031. No significant difference was observed for LDL‐C and cholesterol among genotypes of all variants using different genetic models. The rs599839 variant had a significant association with the severity of coronary stenosis using additive model. The OR was 2.7 times among patients with significant stenosis (p =0.04). Stepwise regression analysis revealed that the following independent variables have a statistically significant effect on LDL‐C level; BMI, diabetes, TC, TG, HDL‐C, and anti‐lipidemic treatment in presence of rs59839 and rs646776 and rs4970834.ConclusionIn summary, polymorphism rs646776 and of rs599839 were significantly associated with HLD‐C and triglycerides levels, but not with LDL‐C. In addition the variant rs599839 had a significant association with atherosclerotic lesion in coronary vessels.
Body weight (BW) and body fat (BF) gain due to ovarian hormone loss is attenuated by inhibiting angiotensin converting enzyme (ACE) or angiotensin type 1 receptors (AT1R) in Dahl salt‐sensitive (DS) female rats
Authors: Ji Hong , Zheng Wei , Bajaj Bilkish , Wu Xie , Liu Jun , Sandberg Kathryn 
Published: June 2021

ObjectiveOvarian hormone loss increases BW and BF gain in women. We and others have shown that ovariectomy (Ovx) increases BW while 17β‐estradiol replacement prevents this effect in DS rats and other animal models. Previous studies implicate the renin angiotensin system (RAS) in BF regulation. Here, we studied the effect of captopril (C), an ACE inhibitor and losartan (L), an AT1R antagonist (0.5g/L each, drinking water) on BW and BF gain induced by Ovx.MethodFemale DS rats were sham‐operated (Sh; n=6) or ovariectomized and treated with vehicle (Ovx), C (Ovx+C) or L (Ovx+L) and maintained on a low sodium (0.01% Na+) diet for 3 months.ResultsAnalysis of lean and fat mass by DXA revealed that while Ovx had no effect on the % lean mass gain, Ovx increased the accumulation of BF (p<0.01 vs Sh) and BW (p<0.0001 vs Sh), while both C & L attenuated these effects [BF (% increase from Sh): Ovx, 139; *Ovx+C, 113; *Ovx+L, 115; *p<0.05 vs Ovx; BW (final‐initial)gm/day: Ovx, 0.40; *Ovx+C, 0.27; *Ovx+L, 0.22; *p<0.01 vs Ovx]. The glucose dysregulation induced by Ovx was also markedly improved by C or L treatment.ConclusionsThese findings suggest that 17β‐estradiol loss causes dysregulation of the adipose RAS and thereby contributes to Ovxinduced BF and BW gain and glucose insensitivity. Supported by AG19291 & HL57502.
Effect of Castration on Cardiac Index in the Spontaneously Hypertensive Rat
Authors: Martin Doug , Kjellsen Barton , Messenger Tami 
Published: June 2021

Androgens amplify the development of hypertension in the spontaneously hypertensive rat (SHR). We showed that androgens increase venous tone, an important contributor to cardiac filling in SHR. The current study tested the hypothesis that castration of SHR would alter the hemodynamic profile during hypertension development in the SHR.SHR were subjected to sham operation, castration or castration+testosterone replacement at 4 weeks of age. Cardiac output was tracked longitudinally using echocardiography. At 6 weeks of age the rats were implanted with radiotelemetry transmitters to monitor arterial pressure and heart rate. These variables were monitored to 13 weeks of age.At 5 weeks of age cardiac index was slightly higher in sham operated (51±5 ml/min/100g) compared to the castrated SHR (40±4 ml/min/100g). Testosterone treatment of castrated SHR partially restored cardiac index (49±8 ml/min/100g). Cardiac index decreased rapidly as the rats aged. At 13 weeks of age there were no differences in cardiac index amongst the groups (Sham: 25±1 ml/min/100g; Castrated 24±2 ml/min/100g; Castrated+testosterone 27±4 ml/min/100g)Collectively, these data are consistent with the possibility that androgens amplify the development of hypertension, at least in part, by increasing cardiac index during the very early stages of hypertension. Supported by NIH #2RO1HL63053‐ARRA (DM).
Metabolite‐detecting and adrenergic gene expression after 40K time trial performance during thermoneutral and heat‐stressed conditions
Authors: VanHaitsma Timothy A , Light Alan R , Light Kathleen C , Hughen Ronald W , White Andrea T 
Published: June 2021

Strenuous exercise may be limited by metabolite detecting receptors on Group IV afferents which heat stress may exacerbate. This study compared mRNA quantities after prolonged intense exercise during thermoneutral (NT) and heat‐stress (HT) conditions on objective markers related to fatigue.Ten cyclists (33.2 ± 3.0 yr, 57.2 ± 1.1 mL/kg/min) performed two 40k time trials; NT (21 C, 10% humidity (RH), temp change (CT) 1.93 C) and HT (35 C, 30% RH, CT 2.10 C). Blood was drawn at baseline, 0.5, 8, 24, and 48 hr after exercise. Leukocytes were separated for qPCR analysis of 5 metabolite detecting receptors (ASIC1, ASIC3, P2X4, TRPV1, TRPV4) and 3 adrenergic receptors (α2a, β1, and β2). Lactates were taken 1 and 5 min post‐ex.Power and post‐ex lactates were lower and exercise time was longer for HT vs NT (p<.001). After both trials, decreases in ASIC3 and TRPV1 were seen (0.5 and 8 hr, p<.05), with larger decreases after NT (p<.05). Post‐ex ASIC3 and TRPV1 were related to 5 min post‐ex lactate (r=‐.50 and ‐.60, p<.01). ASIC1 decreased after NT (0.5, 8, and 48 hr, p<.05). P2X4 decreased after both trials (0.5 hr). TRPV4 decreased after NT (0.5 hr, p<.05) and HT (8 hr, p<.001). α2a increased at 0.5 hr after HT and β2 decreased 0.5 hr after NT.Post‐ex decreases in metabolite detecting genes may represent downregulation of afferent signaling to reduce fatigue sensations. HT produced smaller changes in post‐ex ASIC1, ASIC3 and TRPV1 expression.
Intravenous ascorbic acid does not block the pressor or sympathetic nerve response to ischemic fatiguing rhythmic handgrip exercise
Authors: Muller Matthew David , Drew Rachel C , Cui Jian , Blaha Cheryl , Mast Jessica , Sinoway Lawrence I. 
Published: June 2021

Reactive oxygen species stimulate group IV muscle afferents in rats but the effects of oxidative stress on the exercise pressor reflex in humans is unknown. The purpose of the current study was to determine the effect of intravenous ascorbic acid (Vitamin C) on the exercise pressor reflex in humans. Seven young healthy nonsmokers participated in the current study, which was part of a large protocol in our laboratory. On Day 1, they underwent systemic infusions of saline and then Vitamin C; on Day 2, they underwent a saline time/volume control. Muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure were monitored throughout baseline, ischemic fatiguing rhythmic handgrip exercise, and post‐handgrip circulatory arrest. The change in mean arterial pressure from baseline to fatigue was not different between saline (Δ 35±6 mmHg) and Vitamin C (Δ 31±6 mmHg). Similarly, heart rate (Δ 22±4 bpm vs Δ 26±4 bpm) and MSNA burst rate (Δ 22±6 bpm vs Δ 22±5bpm) were also not different between treatments. Metaboreflex activation and time control experiments similarly showed no treatment effects. The current data suggest that oxidative stress does not contribute to the magnitude of blood pressure or MSNA response seen during fatiguing handgrip in young healthy subjects.This study supported by P01 HL096570 (LIS) and UL1 RR033184 (LIS)
Persistence of inspiratory rhythm in calibrated newborn rat pre‐Bötzinger complex slices upon blockade of store‐mediated calcium signaling
Authors: Ballanyi Klaus , Panaitescu Bogdan , Ruangkittisakul Araya 
Published: June 2021

It is not clear which roles calcium release from cellular stores and subsequent modulation of ion channel activities play in generation of inspiratory rhythm by the bilaterally organized pre‐Bötzinger complex (preBötC) in the lower brainstem.We studied this in transversal newborn rat brainstem slices with anatomically defined location of the <200 μm thin preBötC using suction electrode recording of inspiratory‐related neural population activity combined with contralateral multiphoton/confocal imaging of free cytosolic calcium (Cai). In 400 μm thick slices with centered or caudally exposed preBötC, inspiratory rhythm was not perturbed during 20 min bath‐application of the sarcoplasmic/endoplasmic reticulum calcium ATPase blocker cyclopiazonic acid (CPA, 50 μM) and remained unchanged for further >1 h after return to control solution. In 400 or 700 μm thick slices with caudally exposed preBötC, persistence of rhythm during 50 μM CPA was accompanied by a major Cai rise in presumptive astrocytes (soma diameter ~10 μm) imaged in slice depths of up to 100 μm. Contrary, CAP caused a minor increase in Cai baseline in larger (15–25 μm) neighboring cells that showed inspiratory‐related Cai rises, thus likely representing inspiratory preBötC neurons. CPA attenuated astrocytic Cai rises due to glutamate (0.5 mM) and blocked (oscillatory) Cai rises in response to the metabotropic glutamate receptor agonist t‐ACPD (25 μM), whereas a major and modest response of preBötC neurons to glutamate or t‐ACPD, respectively, persisted in CPA.Our findings indicate that CPA causes store‐mediated calcium release in astrocytes and impairs their metabotropic calcium signaling, whereas inspiratory bursting of preBötC neurons is independent of such calcium stores.Supported by CIHR, AHFMR, CFI‐ISRIP, CIHR‐MFN Health
Brainstem areas activated by intermittent apnea in awake unrestrained rats
Authors: Schoorlemmer Guus H. , Falquetto Barbara , Ferreira Caroline B. , Takakura Ana C. , Moreira Thiago S. , Cravo Sergio L. 
Published: June 2021

Patients with obstructive sleep apnoea experience repeated hypoxia, hypercapnia, and changes in pulmonary afferent traffic, resulting in autonomic activation and hypertension. We analyzed brain areas activated by apnea in conscious rats by c‐fos immunohistochemistry. Wistar rats (n= 9, 300–380 g) were anaesthetized with ketamine + xylazine, and balloon‐tipped catheters were implanted in the trachea. The balloon tip was contained in a rigid thin‐walled Teflon tube, 6 mm long, 2.2 mm diameter. Inflation of the balloon closed the lumen of the Teflon tube, and induced obstructive apnea without inducing pain in the trachea. The free end of the catheter was exteriorized on the rat's back. One week after surgery, five rats were subjected to intermittent apnea (14 s each 2 min) for 1 h, and sacrificed 30 min after the end of apneas for analysis of c‐fos. The four remaining rats were used as controls. Apnea increased the number of c‐fos immunoreactive cells in the parabrachial and Kölliker‐Fuse complex, retrotrapezoid nucleus, commissural and dorsomedial nucleus of the solitary tract and both the rostral (RVLM) and caudal ventrolateral medulla (CVLM). Tyrosine hydroxylase was present in many of the c‐fos positive neurons in the C1 region (69 ± 3%), but not in the A1 or A2 catecholaminergic regions. In conclusion, apnea activates specific brainstem areas involved in autonomic control.Financial support: FAPESP
Integration of the baroreflex control mechanism in a heterogeneous model of the cardiovascular system
Authors: Fernandes Luciano Gonçalves , Trenhago Paulo Roberto , Blanco Pablo Javier , Feijóo Raúl A 
Published: June 2021

The present work describes the mathematical model of the baroreflex receptor mechanism working on a dimensionally‐heterogeneous (1D‐0D) closed‐loop model of the cardiovascular system. Such heterogeneous model includes the 1D description of the arterial tree, 0D model for the venous, pulmonary and cardiac circulation. The detailed description of the arterial vascular tree allow us to perform vasomotor control actions in a different way, while gaining insight about the effects of the baroreflex regulation over hemodynamic quantities of interest throughout the entire vascular system. One example is presented: we simulate the hemorrhage in the abdominal aorta artery and analyze the action of the baroreflex over the system.CAPES, CNPq and FAPERJ
Accelerated Bone Healing in the Absence of TLR4
Authors: Wang Dan , Kubala Adam , Billiar Timothy , Cooper Greg 
Published: June 2021

OBJECTIVEToll‐like receptor 4 (TLR4) is a member of highly conserved receptor family and is a critical activator of the innate immune response after tissue injury. TLR4 signaling has been shown to regulate both the immune response and bone metabolism during long‐bone fracture healing. Unlike defects in long bones, defects in the calvaria often do not heal. Here we tested the hypothesis that the inflammation driven by TLR4 activation limits the healing of calvarial defects.METHODSCircular bone defects were made in the parietal bones using a 1.8mm outer diameter trephine in WT (n=32) and TLR4−/− mice (n=24). Calvarial bone and surrounding soft tissues (e.g. skin and brain) were harvested and bone healing was assessed using histomorphology at postoperative days 0, 1, 2, 4, 7, 14, 21 and 28.RESULTSHistomorphometric analysis demonstrated significantly larger bone healing areas in TLR4−/− mice compared to WT mice on day7 (p<0.001). Similar levels of bone healing were observed by day 28 (p=0.070).CONCLUSIONSThese data are consistent with the hypothesis that TLR4 activation delays calvarial healing in mice. Further work is required to determine if this is due to inflammation driven by TLR4 activation.
Six3 expression is augmented in the facial primordia of mice with misexpression of six2 associated with frontonasal dysplasia
Authors: Hynd Thomas , Fogelgren Ben , Somponpun S. Jack , Fong Sheri F. T. , Lozanoff Scott 
Published: June 2021

We have previously described the Br mutant mouse displaying heritable frontonasal dysplasia. Linkage analysis mapped the mutation near the homeobox transcription factor six2, normally expressed in the facial mesenchyme during development. The purpose of this study is to determine expression patterns of six2, as well as possible upstream and downstream targets of six2, in the developing midface. The three sets of facial prominences (medial, lateral, and maxillary) of E11.5 embryos were dissected and RNA extracted for qPCR assays and microarray analysis. Medial nasal prominences (MNP) were also taken for cell culture. qPCR results indicated six2 expression is highest in the MNP and demonstrated haploinsufficient down‐regulation in each of the three facial prominence sets in the Br mouse. Microarray results suggested the misregulation of several genes in the Br midface, including another member of the Six family of transcription factors: six3. qPCR and immunohistochemistry for six3 substantiated its upregulation in the microarray. Future work using RNA interference on six2 will be used to investigate possible pathways involving six2 and six3. Preliminary results using an in vitro knockdown of six2, performed on an MNP cell culture system utilizing siRNA, demonstrated a 65% knockdown of six2. These results may enable further in vitro work in order to elucidate a pathway in the developing midface involving six2.Grant Funding Source : NIH R01DK064752 (SL) & NCRR 5P20RR024206 (SJS)