bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenylephrine‐induced current and vasoconstriction are blunted in mesenteric arteries of TRPC3 knockout mice
Authors: Pathan Asif R , Bowlin Brandi M , Machaca Khaled , Abramowitz Joel , Zheng Fang , Rusch Nancy J
Published: June 2021

Cationic current mediated by canonical transient receptor potential (TRPC) channels contributes to vascular smooth muscle cell (VSMC) activation. However, the TRPC subtype (TRPC1‐7) that mediates the influx of cations in response to α‐adrenergic receptor activation in the mesenteric circulation has not been established. Here, we used TRPC3 knockout (KO) mice to define the role of TRPC3 channels in phenylephrine (PE) –mediated constriction. Real‐time PCR confirmed the absence of TRPC3 transcript in mesenteric arteries (MA) of KO mice, whereas transcript levels of other TRPC channel subtypes were not significantly different. Diameter reductions in response to KCl (60 mM) were similar between pressurized MA of wild type (WT, 44±5%) and KO (52±9%) mice. However, dose‐dependent contractions to PE were impaired in KO mice (EC50 = 75±4 μM, Emax = 130±7%) compared to WT mice (EC50 = 9±4 μM, Emax = 166±25%). Correspondingly, the mesenteric VSMCs of KO mice showed 52±5% less PE‐evoked current (−1.38±0.16 pA/pF) compared to WT mice (−2.92±0.27 pA/pF). Thus, TRPC3 channels appear to mediate PE‐induced cation entry and vascular tone, consistent with a role in blood pressure regulation. Supported by Grant Z01‐ES101846 from the Intramural Research Program of the NIH (JA), NIH R01 HL064806 (NJR) and NPRP 08‐392‐3‐087 (NJR and KM) from the Qatar National Research Foundation.
Protective effect of anti‐TLR3 monoclonal antibody in Poly(I:C)/D‐galactosamine induced mouse sepsis model
Authors: Li Chen , Guzman Victor , Lee Iris , Liang Yanbin
Published: June 2021

Activation of toll‐like receptor 3 (TLR3) by foreign and endogenous ligands including viral dsRNA, bacterial RNA, mitochondrial RNA, and endogenous necrotic cell mRNA could trigger both apoptosis and inflammatory pathways that lead to disease development. Therefore, the hypothesis was that the blockade of TLR3 activity could be an approach to treat apoptosis and inflammation related disorders. First, anti‐TLR3 monoclonal antibodies were generated using standard hybridoma technology and then screened by Octet binding affinity assay. The antibody, R11H8, which specifically bound to mouse TLR3 receptor with Kd 2.97×10−10 M affinity was identified and expanded for cell‐based functional assays. Using TLR3‐overexpressing stable cell line, R11H8 dose‐dependently blocked poly(I:C)‐induced IL‐8 release (IC50 = 60nM). The mouse sepsis model was induced by administration of D‐galactosamine and poly(I:C). In this model, D‐galactosamine is a hepatotoxin which function as a sepsis sensitizer, and poly(I:C) is a sepsis‐inducing molecule that mimics dsRNA and activates TLR3. R11H8 (1 mg/mouse) was intraperitoneally injected into mice one day before Poly (I:C)/D‐galactosamine induction. Three days after sepsis induction, mice that did not receive the antibody were dead, whereas all of the mice in anti‐TLR3 treated group survived. The result confirmed that the blockade of TLR3 receptor activity could diminish the pathogenesis of dsRNA induced sepsis. The generation of anti‐TLR3 mAb, R11H8, provided a powerful tool for us to better understand the role of TLR3 in the inflammation and apoptosis related disease development.
Impact of rosiglitazone and metformin on serum pro‐inflammatory molecules and adipocytokines in rats with chronic fructose diet
Authors: Sigrist-Flores Santiago , Pardo Juan Pablo , Murguía-Romero Miguel , Villalobos-Molina Rafael , Jimenez-Flores Rafael
Published: June 2021

Metabolic syndrome is a pathological condition involving metabolic abnormalities: abdominal obesity, hyperinsulinemia, dyslipidemia, impaired glucose uptake, all of them linked with increased risk for DM2, and CVD. Those alterations are closely related to a chronic inflammation promoting endothelial dysfunction, and other reactants of acute and chronic phases. Adipose tissue produces adipokines that integrate endocrine, autocrine and paracrine signals, contributing to inflammation. We aimed to explore the in vivo effect of metformin and rosiglitazone in fructose‐fed rats.

We evaluated sICAM‐1, TNF‐α, IL‐6, IL‐1β, C‐Reactive Protein, leptin, adiponectin, and glucose, triglycerides, uric acid, HDL‐C and LDL‐C. Drugs were administered alone or combined for 3 mo, in rats fed 30% fructose for 4 mo. At month 6 with fructose diet, altered glucose, triglycerides and uric acid, were observed. Fructose induced changes in IL‐6 and IL‐1β at month 7, not observed in rats treated with metformin. Combined therapy decreased weight and normalized leptin and IL‐1β. Thus, increase in IL‐6 and IL‐1β after fructose intake, evidence inflammation, normalized by the combined effect of metformin and rosiglitazone, and harmonizes with decreased leptin and weight loss.

Supported in part by grant PICDS08‐69 from ICyT‐G.D.F., México.
Interplay of Epoxides and Heme Oxygenase System Suppress Adipogenic Regulators in Mesenchymal Stem Cell Derived Adipocytes
Authors: Vanella Luca , Abraham Nader G
Published: June 2021

Epoxygenase activity and synthesis of epoxyeicosatrienoic acids (EETs) have emerged as important modulators of obesity and diabetes. We examined the effect of the EET‐agonist 12‐(3‐ hexylureido)dodec‐8(2) enoic acid on Mesenchymal Stem Cell (MSC) derived adipocytes proliferation and differentiation. MSCs expressed substantial levels of EETs and inhibition of soluble Epoxide Hydrolase (sEH) increased the level of EETs and decreased adipogenesis. EET agonist treatment increased HO‐1 expression by inhibiting a negative regulator of HO‐1 expression, Bach‐1. EET treatment also increased catenin and pACC levels while decreasing PPAR C/EBP and fatty acid synthase levels. These changes were manifest by a decrease in the number of large inflammatory adipocytes, TNF, IFN and IL‐1, but an increase in small adipocytes and in adiponectin levels. In summary, EET agonist treatment inhibits adipogenesis and decreases the levels of inflammatory cytokines suggesting the potential action of EETs as intracellular lipid signaling modulators of adipogenesis and adiponectin. NIH‐ DK056601
Deficiencies In Toll Like Receptors 4 Impair The Functional Recovery In A Mouse Model Of Spinal Cord Trauma
Authors: Impellizzeri Daniela , Mazzon Emanuela , Ahmad Akbar , Esposito Emanuela , Cuzzocrea Salvatore
Published: June 2021

Toll‐like receptors (TLRs) are a family of molecules that play a critical role in innate immunity. TLRs can be activated by heat shock proteins (HSPs), necrotic cells, extracellular matrix, and oxidized lipids – all of which are found in the injured spinal cord. Here, using a model of spinal cord injury, we show dramatic induction of TLRs and molecules associated with TLR signaling. The injury was produced by extradural compression of the spinal cord using an aneurysm clip with a closing force of 24 g to the dura via a four‐level T5‐T8 laminectomy in mice. Our present data show that the deficiency of TLR4 in C57BL/10ScN mice (TLR4 knockout) significantly impairs the normal progression of SCI/repair and functional recovery compared with wild type (WT) animals. We evaluated the following points: histological damage, motor recovery, nuclear Factor‐κB expression, cytokines production, inducible nitric oxide synthase (iNOS) expression, neutrophil infiltration, glial fibrillary acidic protein (GFAP) and CD11β expression, nitrotyrosine and poly‐ADP‐ribose (PAR) formation, glial cell‐derived neurotrophic factor (GDNF) expression, apoptosis (Caspase 3, Bax and Bcl‐2 expression). Capable of both protective and pathological roles, TLR4 can be helpful or harmful under varying neurological conditions. When and why TLR4 initiates beneficial outcome is still largely unknown, but progress in the field suggests that this question will receive much attention, as TLR4 is a useful and druggable target.
THE EVALUATION OF BONE PROTEOME OF PALM VITAMIN E‐SUPPLEMENTATION IN OVARIECTOMISED RATS
Authors: Okechukwu Nwabueze Patrick , Mohamed Norazlina , Soelaiman Ima Nirwana , Shuid Ahmad Nazrun , Muhammad Norliza
Published: June 2021

Introduction

Osteoporosis is a common disease characterized by decreased bone mineral density (BMD) and microarchitectural deterioration of bone structure. Supplementation of palm vitamin E for 10 months was able to prevent loss of bone density in ovariectomised female rats. The mechanism by which palm vitamin E exerts these effects is still unknown. One study has found that some proteins were overexpressed in the ovariectomised rats as opposed to the control rats.

Objective

We hypothesized that palm vitamin E may act by preventing the protein expression changes.

Method

The study was divided into five groups; ovaritectomised treated with Palm vitamin E, Olive oil, alpha tocopherol, sham and normal. Femoral bones were harvested for protein extraction. Two‐dimentional gel electrophoresis was performed and proteins were analyzed using software genomic solutions Investigator.

Result and Discussion

Differential protein expression profile reveals that about five (5) protein spots were overexpressed in ovariectomised group treated with olive oil compared the ovariectomised group treated with palm vitamin E. While about three (3) protein spots were not expressed in the ovariectomised group treated with olive oil and were expressed in the group treated with palm vitamin E. The differential protein expression may account for the mechanism through which palm vitamin E exert its anti‐osteoporotic effect. However more research is ongoing to identify the proteins of interest.
Characterization and identification of red diamond back rattlesnake venom proteins
Authors: Joshi Amod N , Krishna Sharath , Grunwald William C , Cool David R
Published: June 2021

Snake venom, although feared for its life threatening effect, is a source of potential bioactive molecules of therapeutic value. While cardiotoxins, myotoxins and neurotoxins constitute the harmful fraction of snake venom; disintegrins and metalloproteinase's are proposed to have anti‐cancer properties. The primary objective of this study is to fractionate, characterize and identify snake venom proteins/peptides. The components of crude venom of Red DiamondBack rattlesnake (RDB) were separated by gel electrophoresis and digested with trypsin. The mass profiling of the digested fractions was carried out using MALDI‐TOF MS followed by identification of proteins using the in‐house MASCOT server. One protein from RDB venom was identified from this initial round of analysis, i.e., the enzyme hemorrhagic metalloproteinase (HT‐2). Our search results showed that HT‐2 had protein scores above the threshold with an indication of 31 percent identity (p<0.05). In conclusion, this approach provides the first round of identification prior to assessing the functionality of individual snake venom proteins as anti‐cancer agents. This work is supported by an NIH grant (1P20MD003350‐04) to Central State University, Ohio.
Morphine decreases neuronal excitability in mouse enteric neurons via alterations in Na+ channel kinetics
Authors: Smith Tricia Hardt , Dewey William L , Akbarali Hamid I
Published: June 2021

A major side‐effect of morphine and other opioids is severe constipation. Morphine decreases neurotransmitter release from myenteric neurons resulting in reduced peristalsis. In this study we used whole‐cell patch clamp techniques to directly study the effects of morphine on cell excitability and ionic currents in mouse enteric neurons. Primary cultures of mouse ileum myenteric neurons were prepared by enzymatic digestion from longitudinal muscle/myenteric plexus (LMMP) preparations and plated in modified Neurobasal A media. Two classes of neurons were identified based on the absence (12/33) and presence (21/33) of an after‐hyperpolarization (AHP) following evoked action potentials. In neurons with AHP, morphine (3 ÂμM) significantly reduced neuronal excitability via an increase in rheobase, a reduction in action potential height, and by inhibiting the neuron from firing multiple action potentials. The resting membrane potential (−51.8 mV) was not affected. The peak amplitude of Na+ currents were significantly attenuated by morphine. The availability of Na+ channels was markedly reduced by morphine as demonstrated by a shift in the steady‐state voltage‐dependent inactivation kinetics. These data demonstrate that inhibition of Na+ current results in reduced excitability of enteric neurons and contributes to the severe constipation concurrent with opioid administration. Supported by NIH DA024009.
Fetal Endothelial Colony Forming Cells Assist Vasculogenesis in the Pregnant Uterus
Authors: Sipos Peter , Rens Willem , Schlecht Helene , Fan Xiaho , Wareing Mark , Baker Philip , Davidge Sandra , Crocker Ian
Published: June 2021

Endothelial Colony Forming Cells (ECFCs) are more robust in the fetus than adult. Uterine blood flow increases in pregnancy, triggering expansion of the uterine vasculature. Fetal ECFCs may contribute to these adaptive requirements.

(i) Fluorescent fetal‐derived cells were tracked in uteri in native female mice mated with eGFP‐expressing males. (ii) Human fetal eGFP‐expressing ECFCs were tracked in uteri of pregnant NOD/SCID mice, whose fetuses had been transplanted with these cells by in vivo intracardiac injection. (iii) In human uterine microvessels of mothers with male offspring, SRY gene was quantified by RT‐QPCR and (iv) Y‐chromosome hybridised in‐situ to localise fetal cells.

(i) Fetal endothelial‐like cells were identified in murine uterine vessels (n=7). (ii) Transplanted human ECFCs (n=8) integrated into the uterine endothelium. (iii) RT‐QPCR detected SRY in 50% of human uterine vessels (n=12). The number of copies corresponded to 246±45 fetal cells/mm2 maternal endothelium (≈10% vessel wall). (iv) Fetal cells were observed in the human uterine endothelium (n=4).

These data suggest that fetal ECFCs assist the vasculogenesis of the pregnant uterus and potentially vascular repair in the mother.
Pentoxifylline reduces myocardial oxidative stress induced by exposure to tobacco smoke
Authors: Azevedo Paula Schmidt , Polegato Bertha , Portugal Priscila , Batista Diego , Lustosa Beatriz , Rafacho Bruna , Oliveira Fernando , Mascoli Alexander , Roscani Meliza , Fernandes Ana Angélica , Zornoff Leonardo , Paiva Sergio , Matsubara Luiz , Pereira Elenize , Minicucci Marcos
Published: June 2021

The objective of this study is to evaluate the role of pentoxifylline (P) in heart remodeling induced by exposure to tobacco smoke (ETS).

Methods

Wistar rats were allocated in 4 groups: C (control); S (smoke); P (diet with P 100mg/kg) SP (smoke + diet with P100mg/kg). After 2 months, animals were submitted to echocardiography, isolated heart study, and oxidative stress evaluation. Two way anova and Holm Sidak tests were performed.

Results

ETS leaded to an increase in left atrium area (p=0,04) and in left ventricle weight (p=0,04) and to impairment of ventricle function that was improved by pentoxifylline as observed in maximum positive derivative (C=3851±245; P=3500±400; S=2725±310; SP=3950± 310) (p=0,01). ETS increased oxidative stress that was attenuated by pentoxifylline: lipoperoxides (C=133,4±14,7; S=175,8±11,5; P=100,0±14,5; SP=128,3±11,9) (p<0,001), Glutathione peroxidases (C=37,4±4,8; S=17,519±3,9; P=33,6±6,4; SP=37,2±5,3) (p<0,001), superoxide dismutase (C=19,4±1,9; S=11,2±0,89; P=16,4±1,6; SP=21,7±2,9) (p<0,001).

Conclusion

It is possible that pentoxifylline attenuates cardiac remodeling induced by ETS, in part due to reduction of oxidative stress.
Short term consumption of a Western diet induces pathological hypertrophy in young mouse hearts
Authors: Medford Heidi M , Marsh Susan A
Published: June 2021

Diets high in sugar and saturated fat (“Western” diet, WES) contribute to the incidence of metabolic syndrome and cardiovascular disease. A hallmark of severe cardiovascular or heart disease is growth of the heart in response to cellular pathology, pressure overload, or tissue damage from myocardial infarction; this is termed pathological cardiac hypertrophy. The development of pathological cardiac hypertrophy in adult hearts is regulated by interactions between repressor element 1‐silencing transcription factor (REST), mSin3A and histone deacetylases (HDAC), and downstream activation of mediators of the fetal gene program, such as atrial natriuretic peptide (ANP) and α‐actin; the fetal gene program is not activated during physiological hypertrophy such as that induced by exercise. To investigate the effects of WES on regulation of cardiac hypertrophy we fed 5 week old C57BL/6 mice either a WES (n=8) or control diet (n=8) for two weeks. WES mice exhibited significantly higher fasting blood glucose and heart wet weight versus control (P<0.05). REST and ANP were higher in WES while α‐actin was lower compared to mice that consumed the control diet. There were no differences in mSin3A or HDACs 1–5. Taken together, these data suggest that even short durations of WES consumption promote pathological rather than physiological hypertrophy and that this may be mediated, at least in part, by the REST complex.
The identification of gene clusters that correlate with vascular adaptations after physical deconditioning and exercise training in humans
Authors: Lammers Gerwen , van Duijnhoven Noortje T. L. , Hoenderop Joost G. , Horstman Astrid M.H. , de Haan Arnold , Janssen Thomas W.J. , de Graaf Mark , Pardoel Elisabeth M. , Verwiel Eugène T.P. , Thijssen Dick H.J. , Hopman Maria T.E.
Published: June 2021

Physical inactivity and exercise training result in opposite adaptations of vascular structure, but the molecular mechanisms behind these adaptations are not completely understood. Therefore, this study examined both vascular characteristics of the superficial femoral artery (using ultrasound) and gene expression levels (from a muscle biopsy). First, we compared able‐bodied controls (n=6) with spinal cord‐injured (SCI) individuals (n=8) to assess the effects of long‐term deconditioning. Able‐bodied controls were also examined before and after short‐term deconditioning using 3 weeks of unilateral limb suspension (ULLS). SCI individuals received 6 weeks functional electrical stimulation (FES) exercise training. Baseline diameter and hyperaemic flow were lower after deconditioning and improved after training, whilst intima‐media thickness/lumen ratio was higher after deconditioning and decreased by training. Gene clusters including the vascular endothelial growth factor (VEGF) pathway (Figure), transforming growth factor beta 1 (TGFB1), and extracellular matrix (ECM) components strongly related with these vascular adaptations. Thus, this approach resulted in the identification of genes that may be involved in structural vascular adaptations after physical (in)activity.

GL was funded by Gelderland‐Overijssel‐EFRO, NTLvD by the Netherlands Heart Foundation, and JGH by the EURYI award.
Late Preconditioning Induced by Transgenic Cardiac Overexpression of α1A Adrenergic Receptors in Rats
Authors: Zhao Xin , Park Jiyeon , ho David , Gao Shumin , Yan Lin , Ge hui , Ilsmaa Siiri , Lin Lin , Tian Bin , Vatner Dorothy , Graham Robert , Vatner Stephen
Published: June 2021

We determined the extent to which cardiac overexpression of the α1A‐adrenergic receptor (AR) in transgenic (TG) rats affords cardioprotection, and if it is involved in first or second window ischemic preconditioning (IPC). Without IPC, infarct size, induced by coronary artery occlusion (CAO) for 30min and 3hrs reperfusion (CAR; expressed as % area at risk), was reduced in TG vs. non‐transgenic littermates (NTL) (35±5% vs 50±2%, P<0.05). After 1st window IPC, induced by 3 episodes of 5min CAO/5min CAR followed by 30min CAO/3hr CAR, infarct size of α1A‐AR TG was reduced further (12±1%) and was similar to NTL (10±1.1%). In contrast, 2nd window IPC, induced by 3 episodes of 5min CAO/5min CAR followed by 30min CAO/3hr CAR at 24 hours after IPC, reduced infarct size only in NTL (29±3%), but not in TG (30±1%), suggesting that TG already exhibited 2nd window IPC. Furthermore, blocking key molecules involved in 2nd window IPC, (iNOS and the MEK/ERK pathway) abrogated cardioprotection in TG rats. Cardiac myocyte microarrays revealed that only 4.6% of 3172 upregulated and 8.8% of 3498 downregulated genes were directionally similar in α1A‐TGs without IPC compared to NTL with 2nd window IPC. Thus, TG rats with cardiac α1A‐adrenergic receptor overexpression exhibit ischemic cardioprotection that resembles 2nd window IPC, with only a minor fraction of overlapping genes.
A Differential Effect of FGF‐2 on Resistance to Doxorubicin‐Induced Necrotic Versus Apoptotic‐Like Damage in Neonatal Rat Cardiomyocyte Cultures
Authors: Wang Jie , Bock Margaret , Cattini Peter A.
Published: June 2021

Therapeutic agents like doxorubicin (DOX), an anti‐cancer anthracycline, can increase the risk of cardiac damage. Strategies are needed to protect the heart that still allows the benefits of drug treatment. “Basic” fibroblast growth factor‐2 (FGF‐2), and specifically the low (18 kDa) molecular weight isoform is cardioprotective, but this has not been reported for DOX‐induced injury. The clinical effects of DOX have been modeled in rat cardiomyocytes, and 0.1–1.0 μM DOX is sufficient to induce cell damage. Here, we assessed the effect of 10 nM FGF‐2 on 0.5 μM DOX‐induced necrotic versus apoptotic‐related damage over 24 hours, as detected by the presence of lactate dehydrogenase in the culture medium (LDH) versus DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). DOX induced a decrease in apparent (attached) cell number and a significant increase in LDH within 6 hours. The remaining cells continued to display muscle striations based on alpha‐actinin staining, but an increase in TUNEL intensity from 6 to 24 hours was also seen. Pre‐treatment (30 min) with FGF‐2 resulted in a significant decrease in LDH but not apparent TUNEL intensity. Additional assays to characterize these effects are being pursued. These data suggest that FGF‐2 can increase resistance to DOX‐induced plasma membrane damage but not DNA fragmentation under the conditions tested.
Voluntary physical activity modulates hypoxia response of sickle cell disease SAD mice
Authors: Martin Cyril , Aufradet Emeline , Pialoux Vincent
Published: June 2021

Sickle cell disease (SCD) is a genetic pathology which is characterized by painful vaso‐occlusive crises triggered by hypoxia and accumulation of poorly deformable red blood cells in the vascular bed. Hemolysis, oxidative stress, inflammatory and vascular adhesion molecules are among the major factors involved in the pathophysiology of SCD. As chronic physical activity may offer the advantage to limit these factors, the aim of this study was to compare, in a transgenic model of SCD (SAD mice), the effect of 8 weeks of voluntary wheel running (VWR) or not (CON) on the response to an acute hypoxic stress (4h at 6.5% O2). The main results of this study showed a significant decrease of the VCAM‐1 immunostaining in SADVWR lungs compared to SADCON (p<0.05). Physical activity in SAD mice (SADVWR) was also associated with decreased cardiac oxidative stress in response to hypoxia. This may be the result of an increased antioxidant GPx activity and/or a decreased hemolysis in SADVWR mice as observed in this study. Furthermore, hypoxia increased the mRNA expression of VCAM‐1, ET‐1 and eNOS in SADVWR but not in SADCON. These results suggest i) that post‐transcriptional regulations, and/or some compensatory mechanisms may occur in SADVWR in response to hypoxia and ii) that habitual physical activity might be beneficial in these mice suggesting possible applications in SCD patients.
Reduced large elastic artery stiffness in older exercising adults is associated with suppressed nuclear factor kappa B signaling
Authors: Jablonski Kristen L , Donato Anthony J , Fleenor Bradley S , Russell Molly J , Walker Ashley E , Seals Douglas R
Published: June 2021

Large elastic artery stiffness increases with age and is a strong independent predictor of incident cardiovascular diseases (CVD) in healthy middle‐aged and older (MA/O) adults. Regular aerobic exercise attenuates this age‐associated stiffening. We hypothesized that suppression of the pro‐inflammatory transcription factor nuclear factor κB (NFκB) may be involved. Aortic pulse‐wave velocity (aPWV) was measured in young sedentary (YS, n=7, blood pressure [BP] 101±3/58±2 mmHg), MA/O sedentary (OS, n=11, 110±4/67±2 mmHg) and MA/O aerobic exercise‐trained (OT, n=12, 120±6/70±4 mmHg) healthy non‐hypertensive men and women. Baseline aPWV increased with age (602±25 [YS] vs. 852±38 [OS] cm/sec, p<0.001) but was 20% lower in OT (686±30 cm/sec) compared with OS (p<0.01). Short‐term (4 d × 2500–4500 mg) treatment with the NFκB inhibitor salsalate (randomized, cross‐over design), reduced aPWV (to 782±44 cm/sec, p<0.05) without changing BP (p=0.74) in OS, but had no effect in YS (599±23) or OT (699±30). Following salsalate treatment, aPWV no longer was significantly different in OS vs. OT (p=0.14). These results support the hypothesis that reduced NFκB signaling contributes to the lower large elastic artery stiffness in MA/O adults who regularly perform aerobic exercise. NIH AG013038, AG006537, AG03114, AG033994, RR025780
Regulation of the pressor reflex response during progressive handgrip exercise in heart failure
Authors: OˈKeefe Zachary Barrett , Witman Melissa A. H. , Richardson Russell S. , Wray D. Walter
Published: June 2021

Exercise intolerance is a hallmark symptom of heart failure (HF), which may be due, in part, to an exaggerated exercise pressor reflex. Thus, the objective of this study was to better define the magnitude and mechanisms of the exercise pressor response in HF. Six HF patients (NYHA Class II‐III) and six young, healthy controls performed dynamic handgrip exercise for 2‐min at 15, 30, 45, and 60% of maximal voluntary contraction. Arterial blood pressure was determined non‐invasively (Finapres), stroke volume (SV) was estimated (Modelflow method), and cardiac output (CO) was calculated as the product of heart rate (HR) and SV. At all exercise intensities, HF patients exhibited an exaggerated increase in mean arterial blood pressure (3±1, 10±1, 15±4, and 24±4 mmHg) compared to controls (1±1, 5±1, 6±1, and 9±2 mmHg). CO increased substantially in the control group (0.2±0.1, 0.3±0.1, 0.6±0.2, and 0.9±0.1 L/min), but was unchanged in HF patients. These findings document an intensity‐dependent augmentation in the exercise pressor response in HF patients. The exaggerated rise in MAP in the absence of increased CO suggests that the exaggerated exercise pressor reflex is expressed exclusively through changes in peripheral resistance, which may contribute to exercise intolerance in this patient population. Research support from NIH PO1 HL‐091830, VA RR&D E6910R, and AHA 0835209N.
Comparison of aerobic capacity and heart rate variability between elite and college soccer players
Authors: Lee Kuan-Ting , Su Chia-Ting , Yang Ai-Lun
Published: June 2021

Aerobic capacity and heart rate variability (HRV) reflect a player's level of the cardiopulmonary fitness and could be used as indicators for predicting the outcome of a player's performance. In this study, we aimed to investigate the differences of aerobic capacity and HRV between the elite and college soccer players. The male elite (n=8) and college (n=18) soccer players, aged from 18 to 25 years, were recruited in this study. Aerobic capacity was determined by the incremental treadmill exercise test. HRV was measured by the short‐range radio telemetry by Polar Electro S810. This study was approved by the Ethics Committee of Taipei Physical Education College, and the informed consent was obtained from all subjects. The body mass index, body fat, and muscular strength were not significantly different between the two groups. The maximal oxygen consumption of the elite players was significantly higher than the college players (p<0.05). Also, the time of 3000 meters running was significantly shorter in the elite group (p<0.05). HRV measures showed that no significant difference of the interbeat interval variability was found between the two groups, but low‐frequency power was lower in the elite players. Our results may provide useful information for assessing the exercise performance in different levels of soccer players.
Lifelong Exercise Improves Cardiac Baroreflex Function But Not Dynamic Cerebral Autoregulation In Older Adults
Authors: Aengevaeren Vincent Laurens , Armstrong Kyle , Palmer Dean , Levine Benjamin , Zhang Rong
Published: June 2021

Previous studies suggest that aerobic exercise training improves cardiac baroreflex function. However, the effects of aerobic exercise training on dynamic cerebral autoregulation (dCA) are not clear. The purpose of this study was to determine the effect of lifelong exercise on cardiac baroreflex function and dCA in older adults. Eleven Masters athletes (MA) (8 males, age 73±6 yrs, aerobic training>15 yrs) and 9 healthy sedentary elderly (SE) (6 males, age 73±4 yrs) participated in this study. Blood pressure (BP), cerebral blood flow velocity (CBFV) and heart rate were measured continuously during resting conditions and repeated sitstand maneuvers. Baroreflex gain was assessed using transfer function analysis of spontaneous changes in systolic BP and RR‐interval in the low (0.05–0.15 Hz; LF) and high (0.15–0.35 Hz; HF) frequency ranges. dCA was assessed using transfer function analysis of induced changes in mean BP and CBFV during repeated sit‐stand maneuvers at 0.05 Hz (10s sit, 10s stand). MA showed higher cardiac baroreflex gain compared to SE (LF: MA: 7.69±7.95, SE: 3.13±1.22, ms/mmHg, P=0.001, HF: MA: 11.13±7.33, SE: 4.11±2.70, ms/mmHg, P=0.006). However, dCA was similar between the two groups (normalized gain: MA: 1.50±0.56, SE: 1.42±0.40, %CBFV/mmHg, P=0.743). These findings suggest that lifelong exercise improves cardiac baroreflex function, but does not alter dCA in older adults.
Effects of one set moderate strength exercise on cardiovascular parameters
Authors: Macedo Fabricio Nunes , de Melo Vitor Ulisses , Santana Michael Nadson Santos , Oliveira Katielle Messenger , Oliveira Larissa Resende , dos Santos Márcio Roberto Viana , Badauê-Passos Daniel , Barreto André Sales , Santana-Filho Valter Joviniano
Published: June 2021

The aim of this study was to investigate the effect of moderate intensity strength exercise (SE) on autonomic balance and spontaneous barorreflex sensitivity (BRS) in rats. We used male Wistar rats (280–320g) that were divided into 2 groups (n=5 for each group): Sham‐(SG) and Trained‐Group (TG). TG rats were subjected to SE (1 set of 10 series with 10 repetitions) in a squat‐training apparatus. SG rats were sham trained. Before SE test, we determined the one‐repetition maximum (1RM), which means the maximum weight lifted by each animal. For this experiment we used sets of 60% of 1RM. The rats were anesthetized (sodium thiopental, 50 mg/kg, i.p.) and the right carotid was instrumented with a catheter for blood pressure (BP) and pulse interval recording. The variability of pulse interval, BP and BRS were analyzed. The SE was able to decrease the mean arterial pressure (MAP) 60 to 90 min (TG = 132 ± 2.7mmHg to 117 ± 1.6mmHg vs SG = 131 ± 2.6mmHg to 129 ± 1.7mmHg) after SE test. SE also reduced LFsys (25% lower) when compared to SG and increased BRS 45 to 90 min after exercise (TG=1.6±0.4mmHg/s to 2.4±0.6 mmHg/s vs SG= 1.9±0.1 mmHg/s to 1±0.07 mmHg/s). SE was able to increase LF/HF ratio (82%) and heart rate (7%). In summary moderate SE was able to reduce MAP despite higher cardiac sympathetic activity observed during all experimental period. Research support: Fapitec‐SE, CNPq, CAPES.
Effects of continuous positive airway pressure on time to fatigue and hemodynamics during sustained heavy exercise in healthy subjects
Authors: da Silva Soares Pedro Paulo , Gonçalves Thiago Rodrigues , Barros Rogério Barbosa , de Tarso Veras Farinatti Paulo
Published: June 2021

The aim of the present study was to investigate the influence of continuous positive airway pressure (CPAP) on time to exhaustion (TLIM), rating of perceived exertion (RPE) and cardiovascular hemodynamics. Healthy male subjects (n= 10, 24±3 years old and VO2max= 41.09 ± 7.37 mL.kg−1.min−1) performed sustained heavy cycling exercise (80%VO2max) with CPAP (20cmH2O of inspiratory and 0cmH2O of expiratory pressures) and without CPAP (NO‐CPAP). There were two days for protocol adaptation (M1 and M2) and two experimental exercise sessions (M3 and M4) executed in NO‐CPAP and CPAP modes, in random order. Exercise days M3 and M4 were used for calculations. Heart rate (HR), systolic blood pressure (SBP) and cardiac output (CO) were obtained by infrared photopletysmograph. The RPE was determined (Borg, 0–10) for dyspnea (B.dys) and for locomotor muscles (B.loc). With CPAP, TLIM increased (555±67 to 639±127 sec, p<0.05) and B.Dys (8±3 to 6±2, p<0.05) and B.Loc (9±2 to 8±2, p<0.05) were reduced as compared to NO‐CPAP. No differences were found for HR (174±13 and 176± 12 bpm, p> 0.05), SBP (210± 32 and 211±21 mmHg, p> 0.05) and CO (16±5 and 15±5 L.min−1, p> 0.05) for NO‐CPAP and CPAP situations, respectively. CPAP during heavy exercise increased TLIM without presenting hemodynamic changes in healthy subjects.

Financial support: CNPq 481434/2008‐9 and FAPERJ E‐26/111.345/2011
Functional Study of Tumor Suppressor p53 Gene Variation: Effect on Cardiovascular Adaptation to Exercise Training
Authors: Kim Boa , Hart Peter , Kang Minsoo , Roth Stephen , Brown Michael D , Hagberg James M , Park Joon-Young
Published: June 2021

Aerobic exercise capacity is inversely related to CVD risk and all cause mortality. p53 plays a crucial role in mitochondrial DNA (mtDNA) maintenance, which is important for mitochondrial function and disease prevention. Here, we extend this concept and investigate whether the p53 codon 72 R/P polymorphism is associated with the adaptive response to aerobic exercise training (AEXT) with respect to enhancing aerobic capacity. 144 sedentary middle‐aged to older females underwent standardized AEXT for 6‐ month. We observed that R allele‐carriers (RR/RP, n = 117) had two‐fold greater improvement in VO2 max in response to the AEXT compared to the non‐carriers (PP, n = 27) (P < .05). To explore the likely molecular mechanisms of p53 being a potential regulator of cardiovascular adaptation to exercise, we further assessed 1) mitochondrial translocation of p53, 2) p53‐mtDNA binding complex, and 3) mtDNA contents in genotyped HUVEC (n = 10, from ten different donors) exposed to exercise‐simulated high flow shear stress (h‐flow, 20 dyne/cm2, 24 h) in vitro. We observed a dramatic increase in mitochondrial p53 level and p53‐mtDNA binding complex under h‐flow (n = 5). Also, RR/RP HUVEC (n = 7) showed significantly higher mtDNA contents compared to PP HUVEC (n = 3) (P < 0.01). Further molecular genetic mechanisms will be discussed. The findings in this study may provide new insights into physiological role of p53 in CV health.
Peripheral Delta Opioid Receptors Attenuate the Exercise Pressor Reflex in Decerebrate Rats
Authors: Leal Anna Katherine , Yamauchi Katsuya , Stone Audrey J , Kaufman Marc P
Published: June 2021

Delta opioid receptors have been identified on group III afferent fibers, which contribute to the mechanically‐sensitive arm of the exercise pressor reflex. We tested the hypothesis that activation of peripheral delta opioid receptors on these afferents attenuated the exercise pressor reflex in decerebrated rats. We measured the cardiovascular responses to static hindlimb contraction before and after femoral arterial injection of DPDPE (1 μg), a delta opioid receptor agonist (n=7). The pressor and cardioaccelerator responses to contraction before DPDPE averaged 18 ± 2 mmHg and 9 ± 2 bpm, respectively and 9 ± 2 mmHg and 2 ± 1 bpm afterwards (both p<0.05). Likewise, femoral arterial injection of DPDPE (1 μg) attenuated the pressor response to tendon stretch, which stimulates group III mechanoreceptors (n=6; pre DPDPE: 9 ± 2 mmHg, post DPDPE: 3 ± 1 mmHg, p<0.05). DPDPE (1 μg) had no effect on the pressor responses to femoral arterial injection of either capsaicin (0.2 μg), a TRPV1 receptor agonist found mostly on group IV afferents (n=8; pre DPDPE: 25 ± 5 mmHg, post DPDPE: 28 ± 5 mmHg) or lactic acid (0.864 mg), an ASIC agonist (n=8; pre DPDPE: 26 ± 6 mmHg, post DPDPE: 20 ± 6 mmHg; both p>0.05). Our data suggests that delta opioid receptors on group III afferent fibers are capable of blocking the exercise pressor reflex.
α‐adrenergic vasoconstriction contributes to the blunted skeletal muscle contraction‐induced rapid vasodilation with aging
Authors: Casey Darren P , Walker Branton G , Mohamed Essa A , Roberts Shelly K , Joyner Michael J
Published: June 2021

We tested the hypothesis that elevated sympathetic tone is responsible for lower peak vasoldilation following single muscle contractions in older adults. Younger (n=8; 5M/3F, age 27 ± 2) and older (n=10; 5M/5F, age 69 ± 2) adults performed single forearm contractions at 10, 20 and 40% of maximum during 1) control, 2) sympathetic activation via lower body negative pressure (LBNP; ‐ 20mmHg), and 3) intra‐arterial infusion of phentolamine (α‐adrenergic antagonist). Brachial artery diameter and velocities were measured via Doppler ultrasound and forearm vascular conductance (FVC) was calculated from blood flow (ml/min) and blood pressure (mmHg). Peak vasodilator responses (ΔFVC from baseline) were attenuated in older adults for all intensities (P < 0.05). LBNP reduced the ΔFVC at 10% (95 ± 18 vs. 60 ± 11), 20% (128 ± 9 vs. 91 ± 18) and 40% (192 ± 21 vs. 133 ± 23; P < 0.01 vs. control) in younger subjects, but not older adults (61 ± 6 vs. 58 ± 10; 99 ± 10 vs. 101 ± 17; 141 ± 17 vs. 129 ± 19, respectively; P = 0.53–0.97). With phentolamine ΔFVC was enhanced in older adults at each contraction intensity (91 ± 12, 136 ± 22, and 181 ± 22, respectively; P < 0.01 vs. control), but not younger adults (87 ± 9, 145 ± 12, and 192 ± 24, respectively; P = 0.31–1.0 vs. control). Our data indicate that overlying α‐adrenergic vasoconstriction plays a significant role in the age‐related decreases in skeletal muscle contraction‐induced rapid vasodilation.
Role of AT2 receptor in the cardioprotective response induced by thyroid hormone
Authors: Barreto-Chaves Maria Luiza Morais , Gomes Dayane Aparecida , Tavares Felix Meira
Published: June 2021

We have shown an upregulation of AT2R in heart from hyperthyroid rats. AT2R has been associated to protection heart function from ischemic injury. This study aims to the role of AT2R in the recovery after Ischemia‐Reperfusion (I‐R) with or without AT2R blockade in isolated heart from hyperthyroid rats. T3 (0.7 μg/Kg BW/day, i.p.) was injected to rats in the presence or absence of AT2R blocker (PD) (10 mg/Kg) for 14 days. Rats were divided in groups: control (C); PD; T3 and PD+T3. Hearts were excised and submitted to I‐R protocol in a Langendorff apparatus. A balloon was inserted in the left ventricle to assess Left Ventricular Developed Pressure (LVDP), +dP/dt and ‐dP/dt. After 30 min of stabilization (S), hearts were subjected to 20 min of I and 45 min of R. Cardiac hypertrophy was assessed by heart weight/tibia length ratio. Data (mean±SD) were analyzed by One‐way ANOVA, considering P<0.05. T3 induced cardiac hypertrophy, which was not changed by PD. Cardiac function after I‐R was analyzed as % of change in the end of R compared to the S period. Data were compared to C group. LVDP increased 35% and +dP/dt 23% in T3 and PD groups; ‐dP/dt increased in T3 (27%) and PD (47%) groups. The combination of treatments (PD+T3) was able to return the heart performance in all parameters to the control situation. In conclusion AT2R plays a significant role in I‐R and it is involved to the cardioprotection induced by T3.
Impaired cavernosal relaxation in Angiotensin‐ II infused mice is improved by deletion of Toll like receptor 4 (TLR4)
Authors: Nunes Kenia Pedrosa , Bonfim Gisele F , Carvalho Maria H , Webb R. Clinton
Published: June 2021

TLRs are important contributors of the innate immune system. TLR‐mediated signaling is involved in inflammatory responses and TLR4 has been associated with cardiovascular diseases (CVD). Erectile dysfunction (ED) is an early marker for CVD. Upregulation of angiotensin II (Ang‐II) is linked with CDV and ED. Ang II is found in human corpus cavernosum (CC) and abnormal levels induce vasoconstriction and endothelial dysfunction. We hypothesize that deletion of TLR4 contributes to improve mice cavernosal relaxation impaired due to Ang‐II infusion. TLR4 knockout (KO) mice and wild type (WT) were infused with Ang II (42 ng/min) for 2 weeks. Functional responses of cavernosal tissue were performed. Cavernosal strips from Ang II WT mice exhibited increased contraction to phenylephrine (PE, 10−8 to 10−4M) and electrical field stimulation (EFS, 1–32 Hz) compared to WT control (CTL), which is attenuated around 25 ± 4.5 % in Ang II TLR4 KO compared to Ang II WT mice. Impaired endothelium‐dependent relaxation to acetylcholine (Ach, 10−9 to 10−5M) in CC from Ang II was improved almost 20 ± 3.7% compared to Ang II TLR KO mice. Furthermore, TLR4 deletion enhanced nitrergic‐induced relaxation in penile tissue from Ang‐II infused mice. In conclusion, these results suggest that TLR4 contributes to impaired penile relaxation and contraction in response to pathological stimulation such as upregulation of Ang‐ II.

Financial support: NIH, AHA.
Hemodynamic and autonomic benefits of exercise training in myocardial infarction persists after 30 days of detraining
Authors: Barboza Catarina , Rocha Leandro Yanase , Dias Danielle Silva , de Souza Romeu Rodrigues , Caperuto Erico Chagas , De Angelis Kátia , Irigoyen Maria Cláudia , Rodrigues Bruno
Published: June 2021

Male Wistar rats were divided in randomized groups: control (C), myocardial infarction (MI)+sedentary (SI), MI+exercise training (ET) (TI), MI+detraining (DI). After 12 weeks of ET, MI size although similar at the begining (~40±3%) was reduced at the end of the protocol in trained and detraining groups (TI: 19±6% and DI: 22±4%) when compared to SI (38±3%). TI group displayed increased maximum speed of running in comparison with C, SI, and DI; however, DI remained increased in relation to SI (C: 2.0±0.1; SI: 1.4±0.08; TI: 2.6±0.1 and DI: 1.9±0.1 Km/h). Basal lactate that was reduced by ET in TI, remained lower in DI as compared to SI animals. ET induced resting bradycardia and increase of mean arterial pressure in TI rats as compared to SI, and these adaptations remained after detraining in DI rats. Baroreflex sensitivity that was normalized by ET, persisted after detraining period, as evidenced by tachycardic (C: 3.2±0.1; SI: 1.9±0.4; TI: 3.0±0.1; DI: 2.9±0.4 bpm/mmHg) and bradycardic (C: 2.0±0.1; SI: 1.4±0.08; TI: 2.0±0.1; DI: 1.9±0.2 bpm/mmHg) responses. These ﬁndings indicate that ET is not only an effective tool in the management of MI derangements but also that these changes were kept working even after 30 days of detraining.
Growth hormone response to the strenuous training in professional skiers has longer recovery time than expected
Authors: Kõks Sulev , Unt Eve , Tillmann Vallo , Fischer Krista , Alaver Mati , Kiudma Tarvo , Terasmaa Anton
Published: June 2021

According to literature, 20–30 minutes recovery period is considered sufficient to normalize growth hormone (GH) levels after exercise stimulation. Aim of our study was to analyze GH response in elite athletes after strenuous training and after 2 hours recovery. We used longitudinal (different years, repeated measures) GH secretion data of 15 skiers (altogether 78 measurements) after very intensive training. Training lasted 3.5 hours with following structure: 0…1 h Lactate (La) <2.5; 1…2h La <3; 2…2:45 La<4; 2:45…3:30 La<8. Exercise induced very high increase in GH level. Mean basal level of GH was 0.9 mU/L (range 11.2 ), after exercise GH level was 22.1 mU/L (range 103.7). After 2 h recovery, GH level was 3.1 mU/L (range 18.7, p < 005 compared to the basal level). Our results show that depending on intensity and individual variability, GH responses to exercise in elite athletes can be much higher than described in the literature.

Conclusion

GH level after strenuous training in professional skiers remain still significantly higher after 2‐hour recovery period compared to the pre‐exercise level. The European Regional Development Fund together with the Archimedes Foundation supported this study.
Exercise training‐induced mitochondrial biogenesis is impaired in skeletal muscle‐specific LKB1 knockout mice
Authors: Hallowell David M. , Tanner Colby B. , Nuttall Megan R. , Anderson Stephen K. , Bradshaw Jared M. , Madsen Steven R. , Thomson David M.
Published: June 2021

Regular exercise training leads to increased mitochondrial protein content in skeletal muscle. The necessity of liver kinase B1 (LKB1) for this adaptation is unknown. Our purpose here was to determine whether skeletal muscle LKB1 is required for exercise training‐induced increases in mitochondrial protein content. To test this, skeletal muscle‐specific LKB1 knockout (KO) and littermate control (C) mice (n=8–9) were either sedentary (SED) or treadmill trained (TRN) 4 days/week, twice per day for 3 weeks. Exercise intensity and duration for both WT and KO mice were determined as tolerated by the KO mice such that the training stimulus was identical for both genotypes. Gastrocnemius (GAST) of TRN C mice had a significant (p ≤ 0.05) increase in the content of the mitochondrial proteins cytochrome‐C and complex I of the electron transport chain (ETC) as well as a trend (p=0.14) for an increase in core 2 of complex III of the ETC. vs. SED C mice. These training adaptations did not occur in TRN KO GAST. We conclude that LKB1 is necessary for increases in some mitochondrial proteins after moderate intensity exercise training. This work was funded by NIAMSD Grant AR‐51928.
Effects of an oral supplementation of omega‐3 polyunsaturated fatty acids on the muscle mass, function, and metabolism under hypoxia
Authors: Dubouchaud Hervé , Le Guen Marie , Chaté Valérie , Pieroni Gérard , Coste Thierry , Pison Christophe
Published: June 2021

Chronic obstructive pulmonary disease (COPD) is associated with patientˈs muscle mass loss and exercise intolerance. An oral supplementation with omega‐3 polyunsaturated fatty acids has been shown to increase exercise capacity in COPD patients. To understand the underlying mechanisms, we studied the effect of docosahexaenoic acid (DHA) oral administration on the muscle function of animals chronically exposed to hypoxia (FiO2 12%) for 3 weeks. Endurance time increased by 210 % in animals under Hypoxia+DHA compared to animals under Hypoxia alone. DHA supplementation preserves the soleus and plantaris muscle masses under Hypoxia despite a similar decrease in total body weight compared to Hypoxia. Oxygen consumption by muscle fibers from soleus using complex I substrate is similar in DHA+Hypoxia and in control (Normoxia) groups but lower in Hypoxia group. This effect of DHA is not seen in white gastrocnemius muscle fibers. Maximal activities and expression levels of respiratory chain complexes are differently affected by Hypoxia and Hypoxia+DHA conditions, suggesting that mitochondria are sensitive to DHA supplementation. These alterations could contribute to the greater exercise tolerance and the muscle mass preservation reported that could justify the use of DHA in patients with muscle mass loss. Further studies are necessary to characterize the action mechanism of DHA on hypoxia‐induced alterations.