bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking wall shear stress with cardiac trabeculation in zebrafish (LB654)
Authors: Lee Juhyun , Fei Peng , Xu Hao , Li Rongsong , Kuo C.‐C. , Ho Chih‐ming , Chi Neil , Hsiai Tzung 
Published: June 2021

Biomechanical forces are intimately linked with cardiac development. Defects in the genetic programming are associated with congenital heart disease such as noncompaction cardiomyopathy. However, the mechano‐transduction mechanism underlying this morphological event remains elusive. Trabeculation starts to develop at 2 days post fertilization (dpf), and it is visualized at 3 dpf in zebrafish embryos. We hypothesized that endocardial wall shear stress (WSS) is implicated in trabecular formation during development. Gata1a morpholino oligonucleotides (MO) micro‐injection reduced erythropoiesis, leading a reduction in viscosity by 70% and consequently, a reduction in wall WSS by 70% via 2D Computational Fluid Dynamics. Similarly, gata2a MO resulted in 90% reduction in viscosity. Using the selective plane illumination microscopy technique, we observed an absence in ventricular trabeculation at 3 dap after gata1a, and gata2a MO injections, in line with that of tnnt2a MO silent heart morphant. Unlike gata1a, gata2a MO injected fish developed reappearance of trabeculation at 4 dfp from a compensatory increase in blood velocity by 32% via particle image velocimetry. Neither gata1a nor tnnt2a MO‐injected fish were able to compensate ventricular WSS with an increase in blood velocity at 4 dpf. Our preliminary finding provides a basis to link shear stress and ventricular trabeculation. Further co‐injection with gata MO and epo mRNA to test gene expression signaling involved in trabeculation would strengthen the mechano‐transduction mechanism.Grant Funding Source: Supported by NIH
Augmented Ca2+‐activated Ca2+ influx and voltage‐gated Ca2+ entry in coronary vs. peripheral conduit arteries in domestic swine. (LB668)
Authors: Bruning Rebecca , Sturek Michael 
Published: June 2021

Intracellular Ca2+ handling has been characterized in a variety of animal models in different vascular beds. However, the extent of regional differences in Ca2+ entry in coronary and peripheral conduit vascular smooth muscle cells (VSM) within an animal model is unknown. VSM were enzymatically isolated from domestic swine coronary (right coronary artery and left anterior descending artery) and peripheral (femoral and popliteal artery) arteries and were digitally imaged using the fluorescent Ca2+ indicator, fura‐2. Cells were exposed to 80 mM K+ in physiologic Ca2+ to assess Ca2+ entry through voltage‐gated Ca2+ channels. Following 80 mM K+ the cells were treated with either physiologic salt solution (PSS) or Ca2+‐free PSS before 5 mM caffeine was used to release intracellular Ca2+ from the sarcoplasmic reticulum (SR). Coronary VSM exhibited a greater response to 80 mM K+ vs. peripheral VSM (2.62±0.03 vs. 2.44±0.04 F360/F380) x minutes). In PSS there was no difference in peak Ca2+ transient elicited by caffeine‐induced Ca2+ store release between coronary and peripheral VSM. In Ca2+‐free PSS peripheral arteries had a smaller caffeine‐induced Ca2+ transient vs. coronary arteries (0.36±0.02 vs. 0.20±0.03 F360/F380). These data suggest SR Ca2+ release elicited greater Ca2+‐activated Ca2+ influx in peripheral artery VSM. Heterogeneous regulation of Ca2+ entry in VSM coronary and peripheral arteries warrants further investigation.Grant Funding Source: NIH R01 HL062552, T32 HL079995
Treatment of insulin resistance‐related cardiac and coronary dysfunction by mineralocorticoid receptor antagonism (LB671)
Authors: Bender Shawn , Padilla Jaume , DeMarco Vincent , Jenkins Nathan , Habibi Javad , Garro Mona , Aroor Annayya , Sowers James 
Published: June 2021

Cardiovascular disease is a major cause of mortality in patients with insulin resistance, a condition associated with renin‐angiotensin‐aldosterone system activation. Mineralocorticoid receptor (MR) antagonists reduce mortality in various populations but the cardiovascular benefit of these agents in insulin resistance remains unclear. We hypothesized that MR antagonism with low dose spironolactone (LSp) would treat cardiac and coronary microvascular dysfunction in insulin resistant obese Zucker (ZO) rats. Obesity, insulin resistance, hyperlipidemia, and blood pressure in ZO rats were not affected by LSp; however, circulating and adipose tissue markers of inflammation were reduced by LSp to levels similar to lean Zucker controls. Impaired cardiac diastolic function, assessed by echocardiography, was corrected by LSp in ZO rats and was associated with reduced cardiac fibrosis and oxidative stress. Similarly, impaired coronary arteriolar vasodilation to acetylcholine and insulin in ZO rats was corrected by LSp involving improved insulin‐mediated Akt phosphorylation. Interestingly, ZO rats exhibited marked immune activation involving decreased presence of Foxp3 gene expression (marker of anti‐inflammatory T regulatory cells) in cardiac tissue which was increased by LSp treatment. These results demonstrate that mineralocorticoid receptor antagonism treats insulin resistance‐associated cardiac diastolic and coronary dysfunction and that these benefits may involve modulation of the immune system.Grant Funding Source: Supported by grants from NIH (HL73101, HL107910) and VA (Merit 0018 and CDA‐2‐2030)
Reversing skeletal muscle dysfunction, hyperhomocysteinemia, and diabetes with exercise (LB679)
Authors: Winchester Lee 
Published: June 2021

Hyperhomocysteinemia (HHcy) induces vascular remodeling and hypertension through production of ROS, MMP‐9, and diminishing NO production. Homocysteine (Hcy) also tends to shift macrophages towards their M1 “pro‐inflammatory” phenotype and away from the M2 “anti‐inflammatory” state, leading to vascular inflammation and hypertension. However, regular exercise acts as a “multi‐pill”, encompassing anti‐hypertensive, anti‐lipid/cholesterolemic, and blood thinning benefits. It reduces Hcy levels in hypertension and diabetes. To test the hypothesis that exercise mitigates hypertension through reduction of Hcy levels and a phenotypic shift from M1 to M2, wild Type C57, MMP‐9 KO, FVB, CBS ‐/+ (HHcy), and Akita (diabetic) mice with and without 4 weeks of exercise are administered a modified swimming protocol. Indices of vascular function were measured using ultrasonography, laser Doppler and tail cuff blood pressure monitoring. Post‐exercise animals were sacrificed. When compared to normotensive animals (C57, MMP‐9 ‐/‐, FVB), the CBS‐/+ and Akita mice have significantly higher baseline blood pressure and smaller luminal diameter with substantially increased wall/lumen ratio. The resistive index was also higher in CBS‐/+ and Akita as compared to controls. The Akita mice demonstrated a significant decline in mean, systolic, and diastolic blood pressure post exercise. Although in FVB (control for MMP‐9‐/‐) mice, we observed a slight but significant decline in mean and diastolic blood pressure, there was no change in MMP‐9‐/‐ group. Our data suggests that Akita and CBS‐/+ mice elicited hypertension and exercise mitigates hypertension in HHcy and diabetes.Grant Funding Source: NIH RO1HL074185
Brachial artery flow‐mediated constriction and dilation in response to a cardiovascular stress: potential influence of age (LB683)
Authors: Freeman Shane , Badrov Mark , Seifarth Joshua , Hanik Sarah‐Anne , Millar Philip , Milne Kevin , McGowan Cheri 
Published: June 2021

Low‐flow mediated constriction (L‐FMC) is a measure of vascular function complementary to flow‐mediated dilation (FMD). L‐FMC is commonly observed in the radial artery, however its presence in the brachial artery is equivocal. Furthermore, the effects of age and an acute cardiovascular stress on L‐FMC are unknown. We measured brachial L‐FMC and FMD (% change) during and following 5‐min of distal forearm occlusion in healthy young (n=7; 29±6 years [mean ± SD]) and old (n=5; 64±5 years) women before and after acute isometric handgrip exercise (IHG; 4, 2‐min unilateral contractions, each separated by 4‐min of rest, at 30% maximal voluntary contraction). Baseline L‐FMC and FMD were similar between groups (Both P>0.05). Acute IHG increased FMD in young (6.7±2.2% to 10.4±3.9%, P<0.05), but not old (7.3±5.4% to 9.7±9.6%, P>0.05) women, while L‐FMC was unchanged (P>0.05) in both groups (young: ‐3.5±6.3% to ‐3.7±4.5%; old: ‐5.5±9.5% to ‐4.0±9.0%). In young women, brachial L‐FMC and FMD were correlated before (r = 0.90; P<0.05) and after IHG (r = 0.97; P<0.05). In older women, L‐FMC and FMD were unrelated before (r = ‐0.20; P=0.74) but trended towards a correlation after IHG (r = 0.82; P=0.09). In conclusion, L‐FMC is observed in the brachial artery of healthy young and old women. Acute IHG appears to restore the relationship between constriction and dilation in old women.Grant Funding Source: Supported by the University of Windsor
Effects of sodium nitrite supplementation on exercise capacity in middle‐aged and older healthy adults (LB689)
Authors: Bassett Candace , Evans Trent , Justice Jamie , Brooks Forrest , Chonchol Michel , Giordano Tony , Seals Douglas , DeVan Allison 
Published: June 2021

Declines in exercise capacity with aging are associated with increased risk of disability and mortality. Dietary interventions that increase circulating nitrite may improve exercise capacity. We performed a pilot study to assess the effects of chronic oral sodium nitrite supplementation (NS) on incremental treadmill exercise performance (modified Balke protocol) in sedentary and recreationally‐active middle‐aged and older (MA/O) healthy adults (n=26, 62±2 yrs). Subjects abstained from dosing for >12 hr before exercise. NS increased plasma nitrite and nitrate (p<0.01). Peak exercise respiratory exchange ratio (RER), heart rate (HR) and ratings of perceived exertion (RPE), markers of voluntary effort, did not differ pre‐post treatment in any group after 10 weeks of NS (80 or 160 mg/d capsules, TheraVasc, Inc., randomized, placebo‐control, double‐blind). NS did not influence maximal oxygen consumption (VO2) (Pl: ‐0.55 ± 2.01; 80mg: 0.41 ± 1.69; 160mg: ‐0.11 ± 1.19 ml/kg/min, p=0.63), although there was a trend for improvement in exercise duration (Pl: ‐0.3 ± 20.0 s; 80mg: +40.9 ± 65.5 s; 160mg: +18.6 ± 28.4 s, p=0.16). There were no significant effects of NS on VO2, HR, RER, RPE or minute ventilation during standardized submaximal workloads. These preliminary results suggest that NS may not increase aerobic exercise capacity or modify responses to submaximal exercise in healthy normally active MA/O adults. It is possible, however, that NS may improve exercise capacity or favorably modify submaximal exercise responses in adults with greater baseline nitrite deficiency (e.g., patients with clinical disease).Grant Funding Source: Supported by NIH HL107105, RR025780, AG000279
The role of O‐linked β‐N acetylglucosamine transferase in cardiac hypertrophy (LB692)
Authors: Miller Lindsey , Medford Heidi , Duenwald Elizabeth , Cox Emily , Marsh Susan 
Published: June 2021

Cardiomyocytes exhibit diminished re‐activation of the fetal gene program (FGP) in response to hypertrophic stimuli due to elevated post‐translational modification of proteins by O‐linked β‐N‐acetylglucosamine (O‐GlcNAc), catalyzed by a single enzyme, O‐GlcNAc transferase (OGT). Repressor element 1‐silencing transcription factor (REST), which associates with OGT, controls FGP transcription. OGT is also involved in transcription via histone modifications such as monoubiquitination and methylation as well as regulation of transcription factor proteolysis, purportedly by the O‐GlcNAcylation to ubiquitination ratio. The objective of this study was to examine the role of OGT in transcriptional control via the ubiquitin proteasome system (UPS) and histone modifications during cardiac hypertrophy. In preliminary studies, upregulation of O‐GlcNAc in isolated adult cardiomyocytes resulted in increased REST and decreased monoubiquitinated histone H2B and protein ubiquitination. Inducible cardiomyocyte specific OGT knockdown (OGT‐KD) and control mice were tamoxifen treated at 5 weeks and sacrificed at 7, 10 and 14 weeks of age. Diminished OGT and protein O‐GlcNAcylation and elevated mRNA levels of FGP components were observed at 7 weeks. Heart weight:tibia length ratio was elevated in OGT‐KD by 10 weeks, indicating decreased cardiac OGT levels result in hypertrophy. Protein ubiquitination was elevated in OGT‐KD hearts. These data suggest that OGT is involved in transcriptional regulation of cardiac hypertrophy via both histone modifications and the UPS.Grant Funding Source: Supported by NIH/NHLBI HL104549
Thyroid hormone upregulates beta‐arrestin 2 (βARR2) expression on cardiomyocytes (LB702)
Authors: Lino Caroline , Barreto‐Chaves Maria Luiza 
Published: June 2021

Changes in thyroid hormone (TH) levels are accompanied by alterations in responsiveness and signaling of G‐protein coupled receptors (GPCRs) in several tissues. β‐arrestins (βARRs) are scaffold proteins primarily involved in GPCRs desensitization. Furthermore, recent studies described that βARRs induce the endocytosis of activated GPCRs and this formed complex may act as a citoplasmatic signaling platform in a G‐protein independent manner. In cardiac tissue, this non‐canonical kind of signaling has been cogitated to be cardioprotective. Considering the beneficial actions of TH on myocardium, we investigated the effect of TH on βARRs isoforms (1 and 2) levels. For this purpose, primary cultures of cardiomyocytes (n=5) were obtained from hearts neonatal Wistar rats by enzymatic disaggregation. The cardiomyocytes were treated for 5 min, 10 min, 15 min, 30 min or 24 h with serum‐free medium (control cells) or with serum‐free medium containing T3 (triiodothyronine, 15ηM, Sigma Aldrich). The βARRs isoforms were evaluated by Western Blot. The data were analyzed by One‐way ANOVA followed by Tukey’s post hoc test. Our data indicate that TH rapidly increased the βARR2 protein levels in cardiomyocytes but no effect was observed after 24h of TH treatment. This preliminary evidence demonstrates for the first time that βARRs signaling is triggered by TH and suggests a possible involvement of this hormone with a new signaling pathway.Grant Funding Source: Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP ‐ grant number: 2013/16142‐9) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Hypercapnia induces dilation of large cerebral arteries and is mediated via a non‐selective cyclooxygenase pathway (LB704)
Authors: Hoiland Ryan , Day Trevor , Wildfong Kevin , Smith Kurt , Bain Anthony , Willie Christopher , Foster Glen , Monteleone Brad , Ainslie Philip 
Published: June 2021

Dogma in human physiology posits that hypercapnia induces arteriolar vasodilation, with little to no vasomotion in large cerebral arteries. Assuming that the middle cerebral artery (MCA) diameter remains unchanged during hypercapnia has validated use of transcranial Doppler ultrasound (TCD) as a surrogate measure of cerebral blood flow. We hypothesized that dilation of the internal carotid artery (ICA) would occur with hypercapnia and be mediated, in part, via a cyclooxygenase pathway. Moreover, we reasoned that MCA velocity (MCAv) reactivity would underestimate ICA flow reactivity. Before and 90 min following oral indomethacin (INDO; 1.45±0.2 mg/kg; mean ± SD), concurrent vascular ultrasound measures of beat‐to‐beat flow, diameter, and velocity through the ICA, and blood velocity in the downstream MCA (n=7) were made at rest and during incremental steady‐state hyperoxic (300mmHg PETO2) hypercapnia (+3, +6, and +9 mmHg PETCO2). The reactivity of ICA flow to hypercapnia (8.2±1.8 %/mmHg) was greater (P<0.01) than the velocity reactivity in the ICA and MCA (5.5±2.5 vs. 4.4±1.3%/mmHg, respectively; P=0.13). This discrepancy between flow and velocity reactivity was explained by a progressive dilation in ICA diameter with hypercapnia (1.0±0.5 %/mmHg). Following INDO, the slope of ICA dilation was reduced by 41.50% (P<0.05). The significance of these findings are: 1) the underestimation of MCAv reactivity compared to ICA flow reactivity suggests that the MCA dilates in response to hypercapnia: and 2) ~40% of hypercapnic ICA dilation is mediated by a non‐selective cyclooxygenase pathway.Grant Funding Source: Supported by the Natural Sciences and Engineering Research Council of Canada
Sodium salicylate rescues inflammation‐associated decrease in phosphorylated‐eNOSser1177 in human aortic endothelial cells through an AMPK dependent mechanism (LB706)
Authors: Siefers Kyle , Wegman‐Points Lauren , Witmer Jordan , Pierce Gary 
Published: June 2021

Obesity is associated with impaired nitric oxide (NO)‐mediated vascular endothelial function (VEF). Pro‐inflammatory cytokines, such as TNF, may contribute to reduced VEF in part through a direct reduction of endothelial NO synthase (eNOS) expression and/or phosphorylation. Sodium salicylate (NaSal), a non‐acetylated aspirin that inhibits nuclear factor B and activates AMP kinase (AMPK), improves VEF in obese humans but the molecular mechanisms remain unclear. We tested the hypothesis that NaSal increases eNOS expression/phosphorylation in TNF‐stimulated endothelial cells through an AMPK‐dependent mechanism. Human aortic endothelial cells (HAECs) incubated in vitro with TNFα (10 ng/ml, 2 hrs) demonstrated decreased (vs. control) expression (Western blotting) of eNOS serine 1177 phosphorylation (p‐eNOSser1177, n=6; P<0.01), eNOS (n=6, P=.078) and phosphorylated AMPK (p‐AMPKThr172, n=2, P<0.05). Pretreatment of HAECs with NaSal (5 mM, 30 min) prohibited the TNF‐stimulated decrease in eNOS (n=4; P=0.77), p‐eNOSser117 (n=4; P=0.1) and p‐AMPKThr172 (n=2; P=0.22). Co‐treatment with the AMPK inhibitor compound C (10 μM, 30 min) abolished the TNF‐induced rescue of p‐eNOSser1177 (n=2; P<0.05) but not eNOS (n=2, P=0.77) by NaSal. These preliminary data suggest that NaSal contributes to increased phosphorylated eNOSser1177 in TNF‐stimulated endothelial cells in part through inhibiting AMPK.Grant Funding Source: Supported by the University of Iowa Fraternal Order of Eagles Diabetes Research Center pilot grant.
Contribution of Ang (1‐7) to Sex Differences in the Renal T cell Profile Following Chronic Ang II Infusion (LB714)
Authors: Zimmerman Margaret , Tipton Ashlee , Baban Babak , Sullivan Jennifer 
Published: June 2021

Angiotensin (Ang) II is pro‐inflammatory, and T cells contribute to Ang II hypertension in male animal models; little is known in females. Initial studies treated 12 wk old male and female Sprague Dawley rats (SD) with Ang II (200 ng/kg/min) and renal T cell profiles were measured via flow cytometry. Ang II increased renal T cell infiltration in both sexes; as well as immuno‐suppressive T regulatory cells (Tregs) only in kidneys of female SD (p=0.004), and male SD had greater increases in pro‐inflammatory Th17 cells (p<0.001). We have previously shown that females also have greater renal Ang (1‐7) levels than males, and Ang (1‐7) has been suggested to be anti‐inflammatory. Therefore, the goal of the current study was to test the hypothesis that chronic Ang II infusion increases renal T cells in both sexes; however, greater Ang (1‐7) results in more Tregs in females than males. Additional male and female SD were treated with Ang II, or Ang II plus the Ang (1‐7) mas receptor antagonist A‐779 (48 µg/kg/hr). CD4+ T cell counts were greater in males compared to females following Ang II infusion (p<0.01), inhibition of Ang (1‐7) did not alter counts in either sex. Ang II infusion increased Tregs in females and Th17 in males, inhibition of Ang (1‐7) did not alter these counts. Renal CD8+ T cell counts were reduced in males relative to females following Ang II infusion (p<0.01), and inhibition of Ang (1‐7) caused a significant but comparable decrease in renal CD8+ T cell counts in both sexes (p=0.0003). In conclusion, our data implicates a role for Ang (1‐7) to modulate Ang II‐induced changes in CD8+ T cell counts; however, our results show that Ang (1‐7) does not mediate the sex difference in Tregs and Th17 in SD during Ang II infusion.Grant Funding Source: Supported by NIH grant 1R01 HL093271‐01A1 to J.C.S, and AHA Predoctoral Fellowship 12PRE11470003 to M.A.Z.
New β‐ENaC Polymorphisms among Salt Sensitive and Salt Resistant Nigerian Subjects (LB718)
Authors: Elias Simiat , Sofola Olusoga , Jaja Smith 
Published: June 2021

The relationship between the β‐T594M polymorphism of the epithelial sodium channel (ENaC) and hypertension remains equivocal. This study was designed to determine the occurence of the β‐ENaC polymorphism among Nigerians as a first step towards determining its importance as a determinant of hypertension in this populace. Forty‐seven normotensive (NT) and fifty‐three age‐matched hypertensive (HT) subjects earlier divided into salt sensitive (SS) and salt resistant (SR) subgroups were recruited for this study. Ethical approval (CM/COM/8/Vol.XXI) was granted by University of Lagos. Blood samples were dried on Whitman filter paper and stored at room temperature until analysed. DNA was isolated from the blood spots followed by ampification by polymerase chain reaction (PCR). The amplicons were thereafter sequenced for β‐ENaC polymorphisms. Polymorphisms were recorded in 13% of the subjects. Five (5%) of the subjects were positive for the β‐T594M polymorphism: 2 NT (both SS) and 3 HT (2 SS and 1 SR).Three new non‐synonymous mutations were recorded among HT subjects: β‐E632V and β‐E636V respectively among two SS HT subjects while β‐D638Y was recorded in an SR HT subject. A fourth new mutation β‐L628Q was recorded in an SS NT subject. A synonymous polymorphysm, β‐T577t was observed in three SS HT subjects and one SS NT subject. The non‐synonymous mutations are likely to be important in the development of salt sensitive hypertension among this populace considering the prevalence (9/100) in such a modest number of subjects. It is of interest that the β‐T594M and the β‐D638Y were also recorded in SR subjects as this might question the relationship between ENaC and salt sensitivity.Grant Funding Source: Supported by International Junior Research Grant of The Physiological Society