bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Intracerebroventricular Leptin Infusion Attenuates Cardiac Dysfunction After Myocardial Infarction
Authors: Gava Fabio N. , da Silva Alexandre A. , Ashraf Sadia , Omoto Ana C.M. , Dai Xuemei , Pullman Mallory , Harmancey Romain , Hall John E. , do Carmo Jussara M. 
Published: June 2021

Leptin is an important regulator of energy balance and substrate utilization in various tissues including the heart. In the present study we tested whether activation of leptin receptors in the central nervous system (CNS) confers protection against cardiac dysfunction after myocardial infarction (MI) induced by permanent ligation of the left anterior descending coronary artery (LAD). Male Sprague‐Dawley rats at 12 weeks of age were implanted with BP telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the lateral ventricle. After 10 days of recovery, mean arterial pressure (MAP) and heart rate (HR) were measured 24‐hrs/day by telemetry and cardiac function was assessed by echocardiography (VisualSonics‐VEVO3100®). After stable baseline measurements for 4 days, the LAD was permanently ligated and saline vehicle (0.5 μL/hr, n=6) or leptin (15 μg/day, n=7) were infused ICV via osmotic minipump for 28 consecutive days. Compared to vehicle treatment, chronic ICV leptin infusion for 4 weeks markedly attenuated cardiac dysfunction caused by MI as evidenced by normalization of global cardiac radial strain (39±4 to 36±5 vs. 37±4 to 25±3 %), cardiac output (92±5 to 110±10 vs. 105±6 to 83±9 ml/min) and left atrium to aorta ratio, an index of cardiac congestion, (1.6±0.1 to 1.6±0.1 vs. 1.7±0.1 to 2.3±0.1). Central leptin administration also significantly improved ejection fraction (from 35±3 to 49±2 %) and fractional shortening (from 12.4±0.8 to 18.6±1.4 %, for week 1 and week 4 post‐MI, respectively), whereas no improvement was observed in vehicle‐treated rats (from 36±4 to 30±2 %, and from 12.2±1.7 to 10.1±1.3 %, respectively). In addition, ICV leptin infusion prevented the bradycardia observed in vehicle‐treated rats (354±3 to 370±6 vs. 360±7 to 323±6 bpm) but did not attenuate the reduction in MAP evoked by MI (101±4 to 94±3 vs. 102±3 to 97±2 mmHg). There was no difference in infarcted area between groups (30±3 vs. 29±5 %). These results indicate that leptin can improve cardiac function and attenuate progression of heart failure after MI via a CNS‐mediated mechanism.Support or Funding InformationNHLBI PO1HL51971, NIGMS P20GM104357 and NIGMS U54GM115428This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RAGE‐DIAPH1 modulates hyperglycemia driven induction of Serum response factor target genes in cardiac cells
Authors: Sreejit Gopalkrishna , Quadri Nosirudeen , Ananthakrishnan Radha , Schmidt Ann Marie , Ramasamy Ravichandran 
Published: June 2021

The mammalian Diaphanous‐related formin diaphanous 1 (DIAPH1) is a canonical effector for Rho small GTP‐binding proteins. When activated by GTP‐bound RhoA, DIAPH1 relies upon its formin homology‐2 domain to elongate linear actin filaments by adding actin monomers to their barbed ends. As a consequence, DIAPH1 also signals to the nucleus via the myocardin‐related transcription factor/serum response factor (MRTF/SRF) axis to effect gene expression. DIAPH1 interacts with the cytoplasmic domain of the receptor for advanced glycation end products (RAGE) through its poly‐proline‐rich formin homology‐1 domain. In response to RAGE ligand stimulation, DIAPH1 participates in signal transduction in smooth muscle cells, macrophages, immune cells, and transformed cells. While RAGE is known to be an essential component of the in vivo response to myocardial stress in diabetes, role of DIAPH1 in diabetic hearts has not been investigated. The goal of this study is to investigate the role of cardiac DIAPH1 in the physiological response to diabetes in mice. In wild type littermate (WT) mice and Diaph1 deleted mice diabetes was induced using low doses of streptozotocin and hearts harvested after 3 months of diabetes. Myocardial Diaph1 expression was significantly increased in diabetic WT mice vs non‐diabetic WT mice (p<0.05). In H9C2 cells, treatment with high glucose (20 mM) and RAGE ligands significantly increased Diaph1 expression. We observed significant increases in expression of a sub‐set of SRF target genes in response to high glucose and that these SRF target genes were attenuated in Diaph1 silenced cells. SRF target genes c‐Fos, Egr‐1, Mmp‐2, Mmp‐9 and Sm‐22, increased in response to high glucose in a DIAPH1 dependent manner, while Tgf‐β1, Tgf‐β2, Atp2a and Cofilin did not show any changes in response to high glucose treatment. We observed that high glucose and RAGE ligands induces DIAPH1 driven changes in SRF target gene expression via ERK1 and PKC αβ signaling mechanisms. We posit that DIAPH1, by its impact on SRF and SRF target genes may play an important role in mediating diabetic cardiomyopathy.Support or Funding InformationNIH HL60901This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Single High Sodium Meal Impairs Dynamic Cerebral Autoregulation
Authors: Migdal Kamila U , Robinson Austin T , Watso Joseph C , Babcock Matthew C , Serrador Jorge M , Farquhar William B 
Published: June 2021

The ability for the brain to maintain cerebral blood flow despite changes in arterial blood pressure is termed cerebral autoregulation (CA). CA is known to be impaired in patients with cognitive decline and in patients that have suffered a stroke. Dysfunctional CA is also predictive of strokes and all‐cause mortality. Excess dietary sodium (Na+) consumption has been implicated in increased stroke risk. However, the effects of a high dietary Na+ consumption on cerebral autoregulation is unknown.PurposeWe tested the hypothesis that a single high‐ vs low‐Na+ meal impairs CA in healthy young adults.MethodsTwenty healthy, normotensive adults (11F/9M; age: 26±5 yrs; BMI: 24.7±3.5 kg/m2; BP: 105±6/58±4 mmHg, mean±SD) participated in this crossover design study. We provided participants with high‐ (HS: 1,495 mg) and low‐(LS: 138 mg) Na+ meals in a randomized order. Visits were separated by one week for males. We tested females in the early follicular phase of their menstrual cycle (~four weeks apart). Right middle cerebral artery (MCA) velocity (via transcranial Doppler ultrasound) and beat‐to‐beat blood pressure (via photoplethysmography) was assessed while participants lay supine for ten minutes. Dynamic CA was measured using transfer function analysis (coherence, gain, and phase) between spontaneous changes in mean arterial pressure to MCA velocity. Transfer function analysis was calculated in the 0.03–0.15 Hz range which reflects cerebral autoregulatory processes. Dynamic CA was measured prior to‐ and 60 minutes post‐meal. Biochemical data from venous blood samples were analyzed using two‐way repeated measures ANOVA (meal x time). Tukey post hoc comparisons were used when appropriate. The change in dynamic CA from baseline was analyzed using paired, two‐tailed, t‐tests.ResultsSerum Na+ was elevated on the high‐ vs low‐Na+ meal 60 minutes post‐meal (HS=141.7±0.8 vs LS=140.2±0.6 mmol/L, p<0.001). Brachial mean blood pressure 60 minutes post‐meal was not different between the conditions (HS=78±5 vs LS=78±7 mmHg, p>0.05). Coherence, gain and phase were not different in the very low frequency band (0.03–0.07 Hz) (p>0.05 for all). The change in gain from baseline in the low frequency band (0.07–0.15 Hz) was significantly elevated following the high‐Na+ meal vs the low‐Na+ meal, implying impaired dynamic CA (HS= Δ0.14±0.46 vs LS=Δ−0.17±0.43 %/mmHg, p=0.02). The change in phase and coherence from baseline was not different between the high‐ and low‐Na+ meals (p=0.33 and p=0.17, respectively).ConclusionThese preliminary data suggest that a high sodium meal may impair dynamic cerebral autoregulation in healthy young adults.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sodium Nitrite Supplementation Improves Vascular Endothelial Function but not Motor or Cognitive Function in Middle‐Aged and Older Adults
Authors: Woodward Kayla A. , Santos‐Parker Jessica R. , Lubieniecki Kara L. , Nagy Erzsebet , Bryan Nathan S. , Chonchol Michel , Justice Jamie N. , Seals Douglas R. , Rossman Matthew J. 
Published: June 2021

We previously observed improvements in vascular endothelial function as well as exploratory measures of motor and cognitive function in a pilot study of sodium nitrite supplementation in middle‐aged and older (MA/O) adults. Here, we sought to establish the efficacy of sodium nitrite for improving endothelial function (primary outcome) while also taking advantage of the opportunity to confirm our motor and cognitive function findings in a larger randomized, placebo‐controlled, double‐blind, parallel group study with 12 weeks of sodium nitrite (80 mg/day) vs. placebo in healthy MA/O adults (n = 49, 68±1 yr) with impaired endothelial function (baseline brachial artery flow‐mediated dilation [FMD] <6%). Sodium nitrite increased plasma levels of nitrite acutely (10‐fold, p<0.05 vs placebo) and chronically (p<0.05) and was well‐tolerated over the 12‐week supplementation period. Vascular endothelial function, measured by brachial artery FMD, was increased by 28% vs. baseline (p<0.05) after 12 weeks of supplementation (3.9±1.2 to 5.0±1.8%, p<0.05), but unchanged with placebo (3.8±1.4 to 4.0±1.5%, p>0.05). There were no differences in secondary outcomes of motor or cognitive function assessed with measures of the NIH Toolbox and other standardized tests between the sodium nitrite and placebo group after 12 weeks (all p>0.05). There were no differences in subject characteristics, body composition or circulating markers of inflammation and oxidative stress with sodium nitrite or placebo (all p>0.05). Collectively, these results indicate that sodium nitrite supplementation for 12 weeks improves endothelial function but does not affect motor or cognitive function in healthy, high‐functioning MA/O adults. These findings suggest therapeutic strategies to enhance nitrite levels may hold promise for treating age‐related vascular endothelial dysfunction.Clinicaltrials.gov Identifier: NCT02393742Support or Funding InformationNIH R01 AG013038, K01 DK115524 and NIH/NCATS Colorado CTSA Grant Number UL1 TR002535; American Physiology Society UGREF AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MG53 Protein Protects Aortic Valve Interstitial Cells from Membrane Injury and Fibrocalcific Remodeling
Authors: Adesanya T.M. Ayodele , Russell Melanie , Park Ki Ho , Zhou Xinyu , Sermersheim Matthew A , Gumpper Kristyn N , Koenig Sara N , Tan Tao , Whitson Bryan A , Janssen Paul M.L. , Lincoln Joy , Zhu Hua , Ma Jianjie 
Published: June 2021

The aortic valve of the heart experiences constant mechanical stress under physiological conditions. Maladaptive valve injury responses contribute to the development of valvular heart disease (VHD). Here we test the hypothesis that MG53, an essential cell membrane repair protein, can protect valvular cells from injury and fibrocalcific remodeling processes associated with VHD. We found that MG53 is expressed in pig and human patient aortic valves and observed aortic valve disease in aged Mg53−/− mice. Aortic valves of Mg53−/− mice showed compromised cell membrane integrity. In vitro studies demonstrated that recombinant human MG53 (rhMG53) protein protects primary valve interstitial cells (VICs) from mechanical injury and that, in addition to mediating membrane repair, rhMG53 can enter VICs and suppress transforming growth factor‐b‐dependent activation of fibrocalcific signaling. Given the preserved contractile function of Mg53−/− mouse hearts under physiological conditions, the observation that aged Mg53−/− mice display hemodynamic and histological signs of aortic valve disease highlights a critical in vivo mechanism of MG53‐mediated valvular protection. Overall, our work revealed a dual function for MG53 in maintaining the integrity of the VICs and in controlling TGF‐β‐mediated fibrotic remodeling associated with VHD.Support or Funding InformationResearch Support: RO1 grants (HL069000 and AR070752) from NIH to J.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Augmented Survival, Angiogenic Properties and Mobilization of Human Endothelial Progenitor Cells Following Exposure to Sevoflurane
Authors: Vlad Adelina , Niculescu Loredan , Stancu Camelia , Popescu Mihaela , Stanca Ionut , Corneci Dan , Ceafalan Laura , Gilca Marilena , Surcel Mihaela , Popescu Andreea , Dimulescu Doina 
Published: June 2021

Anesthetic preconditioning (APC) with volatile agents has cardiac anti‐ischemic virtues that may be linked to stimulating effects of volatile anesthetics on stem cells biology. We investigated the influence of sevoflurane (Sevo) on apoptosis, proliferation, incorporation in tube‐like structure and mobilization of human endothelial progenitor cells (EPCs). 7‐days old cultured EPCs derived from human cord blood mononuclear cells were exposed in vitro to sevoflurane 2% or 4% in air/5% CO2, or only to air/5% CO2 (sham control) for 2 hrs in a modular chamber. Proliferation, apoptosis and incorporation of EPCs into tube‐like structures of HUVEC was evaluated 24 hrs later. EPCs plasma levels were evaluated by flow‐cytometry and in vitro culture assay before exposure to sevoflurane (1 MAC in 50% O2) or only to 50% O2 (sham control) and 24 hrs afterwards, in blood samples collected from coronary artery disease patients. Values are expressed as means ± SEM, compared by ANOVA. In the in vitro preconditioning setting, sevoflurane stimulated EPCs proliferation estimated by the MTS assay (n = 12, p < 0.01 for 2% Sevo, p < 0.001 for 4% Sevo) and by counting adherent DilAcLDL+/ FITC‐UEAI+ cells (n = 4, p < 0.01 for 2% Sevo, p < 0.001 for 4% Sevo), diminished apoptosis measured by annexin V/ propidium iodide assay (n = 5, p < 0.05 for both 2% and 4% Sevo), and raised the number of incorporated DiIAcLDL‐EPCs into HUVEC tube‐like structures (n = 4, p < 0.01 for 2% Sevo, p < 0.001 for 4% Sevo) when compared to control. Plasma CD45dim/CD34+/CD309+ and CD45dim/CD34+/CD309+/CD133+ mononuclear cell populations were increased in Sevo treated patients (n = 15) vs. the control group (n = 10) at 24 h post‐exposure vs. baseline (p < 0.01), and the number of adherent DilAcLDL+/FITC‐UEAI+ cells in 7 days old EPCs cultures was significantly higher in the study group vs. control between the same time points (p < 0.05). Our data prove that sevoflurane positively influences the biology of EPCs both in vivo and vitro, and may have an important cardioprotective impact in various interventional and surgical heart procedures by improving angiogenesis and ischemic tissue repair.Support or Funding InformationThe financial support was provided by UEFISCDI Romania, research grant PN‐II‐RUTE‐2012‐3‐0463.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Impact of Salt Restriction on Central and Peripheral Hemodynamics During Exercise in Essential Hypertension: A Systematic Investigation
Authors: Ratchford Stephen M , Broxterman Ryan R , LaSalle David Taylor , Kwon Oh‐Sung , Hopkins Paul N , Richardson Russell S , Trinity Joel D 
Published: June 2021

BackgroundDietary salt restriction is a well‐established approach to lower blood pressure and reduce cardiovascular disease risk in hypertensive individuals. While high blood pressure increases the risk of cardiovascular events in hypertensive individuals during exercise, little is known regarding the effects of salt restriction on central and peripheral hemodynamic responses to exercise in individuals with hypertension.PurposeTherefore, this study sought to determine the impact of salt restriction on central and peripheral hemodynamic responses to handgrip and knee extension exercise, exercise modalities which circumvent the central limitations to whole body exercise.MethodsHypertensive patients (14M/8F, 51±10y, 173±11cm, 99±23kg) forwent antihypertensive medication use for at least 2 weeks prior to cross‐sectional enrollment on a 5‐d liberal salt (LS: 200mmol/d) followed by a 5‐d restricted salt (RS: 10mmol/d) diet. Patients were studied prior to and during: supine static intermittent handgrip (HG) exercise at 15, 30, 45% MVC (MVC: 20±4kg) and seated knee extension (KE) exercise at 40, 60, 80% KE Max (KE Max: 35±17W).ResultsSalt restriction lowered resting systolic blood pressure (SBP) (supine: −12±3mmHg, seated: −14±3mmHg, P<0.05), diastolic blood pressure (DBP) (supine: −3±2mmHg, seated: −5±1mmHg, P<0.05), and mean arterial pressure (MAP) (supine: −8±2mmHg, seated: −8±2mmHg, P<0.05). Similar reductions in SBP, DBP, and MAP were maintained during HG and KE exercise (all p<0.05). Despite lower blood pressure during exercise, peripheral blood flow and vascular conductance, were similar between groups during HG and KE exercise.ConclusionsSalt restriction appears to be an effective means to ameliorate blood pressure and reduce the risk of a cardiovascular event during exercise in hypertensive individuals without altering blood flow and vasodilatory ability during either arm or leg exercise.Support or Funding InformationVeteran Affairs Rehabilitation Research and Development Grant, 1KRX001215 CDA2, JD Trinity and Merit Grants, E1697R and E6910R, RS Richardson; American Heart Association Grant, 14SDG1850039, JD Trinity; National Heart, Lung, Blood Institute Grant, P01‐HL‐091830, RS Richardson.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Leptin induces hypertension acting via Transient Receptor Potential channel subfamily M member 7 (Trpm7) in the carotid bodies
Authors: Shin Mi Kyung , Caballero Candela , Tang Winnie Yan‐Yee , Yeung Bonnie Ho‐yee , Gu Chenjuan , Sham James S.K. , Shirahata Machiko , Polotsky Vsevolod Y. 
Published: June 2021

RATIONALEObesity leads to cardiovascular morbidity and mortality acting via multiple mechanisms including increased prevalence and severity of hypertension. Obesity leads to high levels of leptin which is produced in adipocytes. Increased leptin levels have also been implicated in increased sympathetic activity and the pathogenesis of hypertension in obesity. However, mechanisms for the effects of leptin on blood pressure are unclear. The carotid bodies (CB) express leptin receptor (LepR), but the mechanisms and consequences of leptin action in CB are unknown. We have previously demonstrated that leptin enhances carotid sinus nerve activity in response to hypoxia and this effect is abolished by non‐selective blockers of transient receptor potential (TRP) channels (Shirahata et al., 2015). We have performed a retrospective analysis of the CB transcriptome in mice and found that trpm7 is the most abundant TRP channel. We hypothesized that high levels of circulating leptin signal via LepR in CB leading to hypertension and this effect will be abolished by trpm7 shRNA.METHODS1) We developed a novel technique allowing us to express LepR in mouse CB using an adenoviral vector suspended in Matrigel. LepR deficient male db/db mice were implanted with telemetry in the left femoral artery for blood pressure monitoring. Blood pressure measurements were performed before and after CB infection with adenovirus carrying the LepR gene (Ad‐LepR, n=5) or luciferase (control, Ad‐Laz, n=6); 2) Male C57BL/6J mice (n=13) were implanted with telemetry for blood pressure monitoring at baseline, during leptin infusion (120ug/day for 3 days via a SC pump) with adenoviral vector which contained trpm7 shRNA (N=6) or control shRNA (N=7);RESULTS1) LepR expression in CB of db/db mice significantly increased mean arterial pressure by 6 mmHg during the day and by 13 mmHg during at night (p < 0.005), whereas CB infection with a control virus had no effect (p=0.585). 2) In C57BL/6J mice, leptin infusion increased mean arterial pressure by 11 mm Hg during the day (p<0.001) and by 15 mm Hg at night (p <0.001). Adenoviral trpm7 shRNA completely abolished leptin‐induced hypertension (p < 0.001).CONCLUSIONSLeptin increases blood pressure acting via LepR in the CB. Leptin‐induced hypertension is abolished by trpm7 shRNA suggesting that leptin may act via TRPM7.Support or Funding InformationHL 133100, HL128970This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Amino Acid‐Based Oral Rehydration Solution Mitigates Exertional Heat Stroke Severity but Does Not Alter the Innate Immune Response
Authors: King Michelle Ann , Dineen Shauna , Ward Jermaine , Mayer Thomas , Plamper Mark , Grosche Astrid , Xu XiaoDong , Sasidharan Anusree , Ward Matthew , Clanton Thomas , Vidyasagar Sadasivan , Leon Lisa 
Published: June 2021

Theadverse sequelae following exertional heat stroke (EHS) is hypothesized to be aconsequence of heat cytotoxicity and endotoxin leakage secondary to increasesin gut permeability. Administration ofspecific amino acids has been shown to tighten the mucosal barrier, reduceparacellular permeability, decrease endotoxin leakage, and suppress the subsequentinflammatory response. The primaryobjective of this study was to determine if an amino acid based oralrehydration solution (AA‐ORS) would increase performance in the heat and dampenthe innate immune response following an EHS protocol when compared to a watercontrol (H2O). To explorethis, C57 BL/6J mice were implanted with temperature transmitters and underwentfour familiarization sessions. On the evening prior to EHS, mice were gavaged with 150 μl of either the AA‐ORS or H2O. The EHS protocol was conducted in an environmental chamber at a temperature of 37.5°C with 30% relative humidity and utilized a forced incremental running protocol. TheEHS protocol continued until neurological symptoms were limiting (core temperature(Tc) 42.2°C ± 0.2 H2O and AA‐ORS). Tissue and blood samples were collected at 0.5, 3, and 24 h post EHS. All mice survived until tissue collection. Performance in the heat was similar between groups as determined by percent dehydration, max speed, distance, time to Tc max, and thermal load (P>0.05). The extent of hypothermia during recovery, a marker of EHS severity, was mitigated with AA‐ORS (P=0.0054). Minimum Tc (AA‐ORS:32.9°C ± 0.4; H2O: 32.1°C ± 0.8; P=0.0020), hypothermia depth (AA‐ORS: 33.3 ±0.5 min; H2O: 32.5 ± 0.8 min; P=0.0024), and hypothermia length (AA‐ORS: 186.9 ± 47.3 min; H2O: 243.6 ± 42.3 min; P=0.0017) were all significantly improved by AA‐ORS. Although AA‐ORS reduced paracellular permeability (4 kDa FITC, Ussing chamber) at both the 30 min and 3 h timepoints (P<0.05), it did not affect the cytokine or chemokine profile (25 plex Luminex panel) in response to EHS at any time point (P>0.05). Inflammation in hypothalamus was alsomeasured as an indication of EHS severity. No differences were seen between AA‐ORS and H2O in mRNA upregulation of IL‐1β, IL‐6, TNFα, MCP‐1, MIP‐1α, MIP‐1β or pattern recognition receptors TLR‐4 and CD14 at the 0.5 or 3 h time points. Further, corticosterone, a hormone that has been shown to suppress the innate immuneresponse, did not differ between treatment groups at any time point. These results suggest that an AA‐ORS improves Tc regulation during EHS recovery, but this dosage had no effect on the systemic inflammatory response that isc haracteristic of EHS. Author views not official US Army or Do Dpolicy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.