bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is preeclampsia all in the head? First‐trimester prediction of preeclampsia via maternal plasma levels of the vasopressin pro‐segment copeptin (860.20)
Authors: Santillan Mark , Santillan Donna , Scroggins Sabrina , Min James , Leslie Kimberly , Hunter Stephen , Zamba Gideon , Gibson‐Corley Katherine , Grobe Justin 
Published: June 2021

Background: Preeclampsia, a devastating gestational hypertensive disorder, is characterized by low circulating renin relative to normal pregnancies. Vasopressin plays an important role in selected low‐renin hypertensive states. Therefore, we hypothesized a role for vasopressin in preeclampsia. Methods: Copeptin, a biologically inert, 4 kDa pro‐segment of vasopressin with a stable and slow plasma elimination rate, is secreted in a 1:1 molar ratio with vasopressin. In this case‐control study, copeptin was measured in banked maternal plasma throughout pregnancy from women who did or did not develop preeclampsia. Results: Maternal plasma copeptin was significantly elevated in all trimesters in pregnancies that did (n=51) or did not (n=30) develop preeclampsia (first trimester: 903 vs. 2045 pg/mL, p=0.008; second trimester: 706 vs. 1806, p=0.02; third trimester: 822 vs. 1890, p=0.0006). While controlling for covariates such as age, BMI, chronic hypertension, twin gestation, diabetes, and history of preeclampsia, the association of elevated copeptin and the development of preeclampsia remained significant. ROC analyses reveal that copeptin is significantly predictive of the development of preeclampsia in all trimesters. Further, vasopressin infusion was sufficient to generate preeclampsia phenotypes in pregnant C57Bl/6J mice. Conclusions: These data establish copeptin as a potent predictor of preeclampsia throughout pregnancy, as early as the first trimester (AUC=0.80, p=0.005, at a cutoff of 1018 pg/mL). The temporal order of changes in copeptin (in early first‐trimester) versus other known mechanisms of preeclampsia (mid‐ or late‐pregnancy) supports our working hypothesis that vasopressin secretion may precipitate or induce other known humoral, vascular, immune, and morphological mechanisms of preeclampsia.Grant Funding Source: HD000849, RR024980, HL098276, HL084207
Aging‐related loss of skeletal muscle strength: the role of muscle quality (863.8)
Authors: Barbat‐Artigas Sebastien , Pion Charlotte , Gouspillou Gilles , Belanger Marc , Hepple Russell , Morais Jose , Aubertin‐Leheudre Mylene 
Published: June 2021

Objective: Skeletal muscle aging is associated with a progressive loss of mass and strength. In this process, the loss of muscle quality has been suggested to cause a disproportionate loss in muscle strength compared to the loss in mass. This study aimed at investigating the role of changes in muscle quality in the loss of muscle strength with aging.Methods: Ten young (24±3 yo) and 9 old (72±4 yo) active men were recruited and matched for physical activity levels. Body composition (DXA and MRI) and knee extension strength (KES) were assessed. Muscle quality indexes (quadriceps mass/KES, volume/KES and CSA/KES) were then calculated. Muscle biopsies were performed in the vastus Lateralis to assess fiber type proportion and size, and intracellular lipid content (Oil Red O).Results: KES, quadriceps mass, volume and CSA were lower in old vs. young adults (p<0.05). Fat mass percentage was higher in old vs. young adults (p<0.05), while total body weight was similar. No differences were observed between young and old men in muscle quality indexes, intracellular lipid content, fiber size and type proportion. However, type IIa fibers tended to be smaller in old than in young adults (p=0.052).Discussion: Our results suggest that, in active old men, the loss in muscle strength is mainly attributable to a decrease in muscle mass. Physical activity may contribute to the preservation of the quality of contraction per unit of muscle.
Lower soluble RAGE and higher aortic stiffness in African American adolescents: possible protective effect of higher sRAGE in white youth (867.10)
Authors: Tank Ericka , Wegman‐Points Lauren , Siefers Kyle , Guinter Mark , Pajaniappan Mohana , Darracott Katherine , Pierce Gary 
Published: June 2021

Advanced glycation end‐products (AGEs) are associated with increased aortic stiffness and cardiovascular disease (CVD) risk in middle‐aged/older adults. AGEs increase cross‐linking of extracellular matrix (ECM) proteins and binding to the Receptor for AGE (RAGE) activates vascular pro‐inflammatory/oxidant signaling. Matrix metalloproteinases (MMPs) degrade vascular ECM proteins such as elastin and cleave cell surface receptors such as RAGE. The cleaved soluble isoform of RAGE (sRAGE) serves as a ‘sink’ for circulating AGEs, so that low sRAGE is associated with increased CVD risk and high sRAGE may be vascular protective. Interestingly, sRAGE is lower in African‐American (AA) compared with white middle‐aged/older adults and is hypothesized to contribute in part to higher CVD risk in AAs. However, it is unknown if lower sRAGE is present in AA youth and associated with increased aortic stiffness. Circulating sRAGE was significantly lower in AA (n=20, age 16.8±1.4 yrs; BMI 24±3 kg/m2) compared with white (n=24; age 16.5±1.5 yrs; BMI 23±4 kg/m2) healthy adolescents (930 ± 432 vs. 1567 ±338 pg/ml, P<0.01), in the absence of differences in blood pressure (BP), AGEs, MMP9 and MMP2 (P>0.05). Aortic stiffness (carotid‐femoral artery pulse wave velocity, CFPWV) was higher in AA compared with whites (5.9±0.9 vs. 5.3±0.8 m/sec, P<0.05). After adjusting for age, BMI and mean BP, sRAGE was negatively correlated with CFPWV only in females (r=‐0.60, P<0.01) mostly from the relation among white (r=‐0.86, P<0.01) and not AA (r=‐0.51, P=0.16) females. In males, MMP2 was positively correlated with CFPWV (r=0.53, P<0.05) and sRAGE (r=‐0.54, P<0.05). Young AAs demonstrate lower circulating sRAGE and higher aortic stiffness compared with their white age‐ and BMI‐ matched peers. Whether lower sRAGE contributes to aortic stiffness in AAs or higher sRAGE has a vascular protective effect on large elastic arteries in whites deserves further investigation.Grant Funding Source: Supported by APS Undergraduate Research Fellowship; Univ of Iowa ICRU Fellowship; GHSU CHDI
Collagen C‐peptide roles in post‐myocardial infarction remodeling (867.15)
Authors: de Castro Bras Lisandra , DeLeon‐Pennell Kristine , Ma Yonggang , Yabluchanskiy Andriy , Iyer Rugmani , Fields Gregg , Lindsey Merry 
Published: June 2021

Collagen type I is the main extracellular protein present in the left ventricle (LV). The aim of this study was to determine the mechanisms whereby collagen peptide (C‐peptide 1158/9), initially generated by several proteases and later degraded by matrix metalloproteinase (MMP)‐9, mediates LV remodeling following myocardial infarction (MI). We performed cleavage assays of recombinant collagen type I by MMP‐2, ‐8, ‐9, and ‐11. MMP‐2, ‐8, and ‐9 all cleaved collagen, but only MMP‐2 and ‐9 formed peptides <24 kDa. Increased doses of MMP‐9 resulted in further degradation of the <24 kDa collagen peptides. The cleavage products were analyzed by mass spectrometry and the MMP‐2/9 cleavage site was identified (aa1158/9). In vitro, C‐peptide 1158/9 stimulated cardiac fibroblast wound healing, suggesting a role in cell migration. In vivo, we found higher levels of the C‐peptide in MMP‐9 null infarcted LV (LVI) at day 5 post‐MI compared to wild type, indicating accumulation of peptide in the absence of MMP‐9. C‐peptide 1158/9 in vivo treatment attenuated LV dysfunction at day 7 post‐MI, evidenced by higher ejection fraction compared to saline MI. In summary, C‐peptide 1158/9 improved LV function by stimulating the cardiac repair response.Grant Funding Source: Supported by POST14350034, HHSN 268201000036C, R01 HL075360, HL051971, 5I01BX000505
microRNA‐378 inhibition promotes angiotensin II induced cardiac hypertrophy and fibrosis: role of paracrine signaling from cardiomyocytes to cardiac fibroblasts (868.1)
Authors: Gupta Madhu , Nagalingam Raghu , Noor Mariam , Sundaresan Ravi , Gupta Mahesh , Solaro R 
Published: June 2021

MicroRNAs play significant roles in cardiac remodeling during heart failure. We have recently shown that miR‐378 is mainly expressed in cardiac myocytes (JBC 2012;287(16):12913‐26) and its over‐expression counteracts cardiac hypertrophy (JBC 2013;288(16):11216‐32). Intriguingly, whole body knockout of miR‐378 has also shown benefits against high fat diet induced obesity. However, cardiac effects of miR‐378 deficiency remain unknown. We examined cardiac response of miR‐378 depletion in mice 7 days following 3 consecutive injections (70 mg/kg, i.p.) of LNA‐ modified 378‐antimiR. We found induction of hypertrophy markers and fibrotic gene expression, and de‐repression of targets, IGF1R and Grb‐2. Ang‐II‐induced cardiac dysfunction and remodeling was drastically enhanced by 378‐antimiR treatment. Inhibition of miR‐378 alone led to induction of TGFβ1 expression in mouse hearts. It stimulated TGFβ1 promoter activity via inducing AP‐1 transcriptional activity and Ras‐signaling. Conditioned medium (CM) of miR‐378 depleted cardiomyocytes resulted in cardiac fibroblast cell differentiation with enhanced fibronectin (FN) and collagen (Col1) expression, which was blocked by inclusion of TGFβ1‐neutralizing antibody in the CM. MiR‐378 over‐expressing cardiomyocytes were found to secrete miR‐378 in the culture medium. The secreted miR‐378 was effectively taken up by cardiac fibroblasts where it repressed AngII‐stimulated FN and Col1 expression. Our findings disclose a new paracrine role of cardiac myocytes in the control of fibroblast cell differentiation involving miR‐378. Our data demonstrate that miR‐378 inhibition promotes adverse ventricular remodeling. Thus, previously suggested therapeutic targeting of miR‐378 in metabolic disorders should be exercised cautiously as it could have deleterious cardiac consequences particularly in conditions of preexisting cardiac disorders.Grant Funding Source: NIH/NHLBI 5R01HL022231‐35
Diaphragm muscle denervation following mid‐cervical contusion injury (871.6)
Authors: Alvarez‐Argote Santiago , Mora Juan , Stowe Jessica , Sieck Gary , Mantilla Carlos 
Published: June 2021

Respiratory failure is one of the most important complications of cervical spinal cord injury. The level of injury critically determines the severity of the complications. We hypothesized that higher cervical contusion injuries will compromise the motor neuron pool and the descending bulbospinal projections, causing greater functional compromise than contusions at lower levels. Unilateral contusion was performed on adult rats at either the C3 or C5 levels vs. laminectomy. No deficit was seen in ventilatory and non‐ventilatory behaviors as assessed by whole body plethysmography or chronic diaphragm electromyography up to 2 weeks. Contusion injuries at either level resulted in similarly sized cavity formation. Phrenic motor neuron loss differed, with C3 contusion causing a 50% loss of phrenic motor neurons, and C5 contusion only 20% loss compared to the contralateral side. The percent of NMJs that were denervated followed a segmental pattern. Following C3 contusion, ventral regions of the diaphragm displayed denervation of ~30% of NMJs compared to 1‐3% in the C5 contusion and laminectomy groups. In contrast, following C5 contusion, denervation was evident only in dorsal regions (~10%). These results show minimal ventilatory impairment following contusion injuries to the mid‐cervical spinal cord that result in phrenic motor neuron loss and evidence of diaphragm muscle denervation.Grant Funding Source: Supported by NIH grant R01 HL096750 and the Mayo Clinic
Effects of acute intermittent hypoxia on sympathetic and expiratory activities in rats (872.8)
Authors: Lemes Eduardo , Bassi Mirian , Colombari Débora , Colombari Eduardo , Zoccal Daniel 
Published: June 2021

The exposure to acute intermittent hypoxia (AIH) produces a long‐lasting increase of phrenic and sympathetic activities in anesthetized rats. In the present study we aimed to evaluate the effects of AIH on baseline expiratory motor activity as well as the role of retrotrapezoid nucleus in the AIH‐induced sympathetic and respiratory changes. In the in situ working heart‐brainstem preparations of juvenile rats (n=4), AIH exposure (10 x 5‐7% O2 for 30 s, every 5 min) increased baseline phrenic (Δ: 20±6%), abdominal (Δ: 65±30%) and sympathetic (Δ: 89±48%) nerve activities (P<0.05) that was maintained for at least 60 min after the last hypoxic episode. In conscious adult rats (n=9), AIH evoked an increase in baseline arterial pressure (Δ: 7±2 mmHg), associated with enhanced sympathetic‐ and respiratory‐related variabilities (P<0.05). In adult urethane‐anesthetized rats with intact vagus (n=5), AIH increased baseline arterial pressure (Δ: 9±1 mmHg) and abdominal muscle contraction amplitude (Δ: 412±117%), which were reverted by pharmacological inhibition of retrotrapezoid nucleus (P<0.05). These data indicate that AIH promotes a sustained increase of expiratory activity, in addition to inspiratory and sympathetic activities. Moreover, AIH‐induced sympathetic and expiratory long‐term facilitation may involve, at least in part, the activation of the retrotrapezoid nucleus.Grant Funding Source: Supported by FAPESP (09/54888‐7; 11/20040‐1) and CNPq
Carotid body induced post‐inspiratory neuron channelopathy for neurogenic hypertension (872.9)
Authors: Moraes Davi , Machado Benedito , Paton Julian 
Published: June 2021

Post‐inspiratory (post‐I)‐modulation of sympathetic outflows was increased in the pre‐hypertensive spontaneously hypertensive (SH) rats and this excitation can be reduced by carotid body denervation (CBD).In SH and Wistar rats (4‐6 week old), simultaneous recordings of sympathetic and respiratory nerves together with whole cell patch clamp recordings of Bötzinger Complex post‐I neurons from in situ preparations were made. We evaluated whether enhanced post‐I modulation of sympathetic activity is due to changes in the intrinsic ionic properties of post‐I neurons and whether this can be reversed by CBD. In SH rats, the increased post‐I modulation of lumbar sympathetic nerve (n=22) was associated with a greater post‐I discharge in laryngeal motor outflow (n=15). These changes are associated with an increased intrinsic excitability and decreased spike frequency adaptation of post‐I neurons in SH(n=8) relative to Wistar (n=8) rats; this was attributed to a reduced calcium activated potassium conductance in SH rat post‐I neurons. Five days after CBD in SH rats the calcium activated potassium conductance in post‐I neurons was similar to that measured in Wistar rats (n=10). Our data support the novel concept of “respiratory neuron channelopathy” mediated by carotid body over activity in SH rats that may contribute to their excessive sympathetic activity.Grant Funding Source: Supported by British Heart Foundation and FAPESP
Angiotensin behaves like a paracrine mediator in guinea pig enteric nervous system (874.1)
Authors: Wood Jackie , Wang Xi‐Yu , Wang Guo‐Du 
Published: June 2021

Enteric mast cell hyperplasia occurs in inflammatory bowel disease and the irritable bowel syndrome. Mast cell proteases are catalysts for conversion of angiotensin I to angiotensin II (AT‐II). We applied AT‐II to ENS neurons, while recording neuronal electrical and synaptic behavior. The AT‐II acted to elevate or suppress neuronal excitability. Suppression of was reversed by noradrenergic alpha2 receptor blocking drugs. AT‐II enhanced electrically‐evoked noradrenergic inhibitory postsynaptic potentials and suppressed fast and slow excitatory postsynaptic potentials. Selective AT‐II1 receptor blocking drugs, but not selective AT2 receptor antagonists, suppressed all actions of AT‐II. AT2 receptor protein and the AT2 mRNA transcript were expressed in the ENS. The AT1 receptor was not expressed. Immunoreactivity for the AT1 receptor was expressed by ENS neurons with AH‐type 2 and S‐type electrophysiological behavior. Our results predict that mast cell‐induced AT‐II formation will have paracrine function in the ENS that includes enhanced release of norepinephrine from sympathetic postganglionic axons. Elevation of norepinephrine represses excitatory neurotransmission in the neural networks of the brain‐in‐the‐gut and suppresses neurogenic secretion thru inhibition of excitability of secretomotor neurons in the submucosal division of the ENS.Grant Funding Source: Supported by National Institutes of Health, R01DK037238
Cardiovascular effects of chronically increasing angiotensin II type 2 receptor expression in the nucleus of the solitary tract (874.2)
Authors: Ruchaya Prashant , Blanch Graziela , Speretta Guilherme , Freiria‐Oliveira André , Sumners Colin , Menani José , Colombari Eduardo , Colombari Débora 
Published: June 2021

The aim of this study was to investigate the effects of increased angiotensin II type 2 receptor (AT2R) expression in the nucleus of the solitary tract (NTS) on neurogenic hypertension. Ten week old normotensive (NT) Holtzman and spontaneously hypertensive rats (SHRs) were microinjected in the NTS with either AAV2‐CBA‐AT2R or AAV2‐CBA‐eGFP (n=5‐8/group). Telemetry and baroreflex were performed on four experimental groups: NTeGFP, NTAT2R, SHReGFP and SHRAT2R. At termination brains were harvested for RT‐PCR. No significant change in mean arterial pressure (MAP) was observed in all groups from baseline to 4 weeks post viral transfection, but SHReGFP and SHRAT2R showed a significant elevation in MAP compared to NTeGFP and NTAT2R groups (138 ± 4 and 136 ± 4 vs. 94 ± 2 and 97 ± 6 mmHg, respectively). SHReGFP showed a significantly impaired baroreflex compared to NTeGFP and NTAT2R (‐0.5 ± 0.1 vs. ‐1.1 ± 0.1 and ‐1.4 ± 0.1 bpm/mmHg, respectively). SHRAT2R show significant improvement in baroreflex compared to SHReGFP (‐0.70 ± 0.1 vs. ‐0.5 ± 0.1 bpm/mmHg, respectively). SHRAT2R have significantly higher mRNA levels of MAS and angiotensin converting enzyme 2 (ACE2) compared to SHReGFP (MAS: 1.6 ± 0.1 vs. 0.7 ± 0.3 and ACE2: 8.5 ± 1.6 vs. 2.0 ± 0.4). While AT2R is ineffective at modulating chronic MAP, the baroreflex is significantly improved in SHR possibly via the MAS/ACE2 axis, suggesting a potential beneficial effect of AT2R.Grant Funding Source: Supported by: CNPq/PRONEX, FAPESP/PNDP‐CAPES, NIH HL‐076803
Circulating Ang II modulates the effects of exercise training on skeletal myopathy in heart failure (874.8)
Authors: Gomes‐Santos Igor , Fernandes Tiago , Couto Gisele , Ferreira‐Filho Julio , Salemi Vera , Fernandes Fernanda , Casarini Dulce , Brum Patricia , Rossoni Luciana , Oliveira Edilamar , Negrao Carlos 
Published: June 2021

Previous studies show that angiotensin II (AngII) mediates muscle wasting. In chronic heart failure (CHF), exercise training reduces AngII and improves skeletal myopathy. Unknown is whether the improvement in skeletal myopathy in CHF provoked by exercise training depends on AngII reduction. Thus, we studied the effects of exercise training on muscle ubiquitin‐proteasome pathway in CHF rats submitted to an AngII clamp (osmotic minipump). Male Wistar rats underwent coronary artery ligation for CHF induction. At fourth week of surgery, the CHF rats were divided into three groups: 1) Untrained; 2) exercise‐trained and 3) exercise‐trained with AngII. Exercise training was conducted on a treadmill 60min/day, 5 days/wk at 60% VO2max during 8wk. Exercise training reduced E3a, Atrogin and MuRF mRNA expression (RT‐PCR), carbonylated and ubiquitinated proteins (Western Blot), and 26S proteasomal activity (Fluorimetry) in plantaris muscle of CHF rats. AngII infusion, set at the same levels of untrained rats, restrained the exercise‐mediated changes in the ubiquitin‐proteasome pathway. We concluded that circulating AngII modulates the effects of exercise training on skeletal myopathy in CHF.Grant Funding Source: Supported by FAPESP (2010/50048‐1), CAPES, CNPq, and Fundação Zerbini
Microglia, a new cellular factor, in the development of hypertension (875.6)
Authors: Li You , Li Liang , Bernstein Kenneth , Shen Xiao , Shi Peng 
Published: June 2021

The concept of neuroinflammation in the development of hypertension has been acknowledged recently, as studies showed that anti‐inflammation treatments attenuated Ang II induced blood pressure increase. Microglia are the major immune cells in the central nervous system. To examine the role of microglia in hypertension, we applied a microglial depletion strategy by using a transgenic mouse line CD11b‐DTR. This mouse line has an inserted transgene coding simian diphtheria toxin receptor (DTR) under the control of the CD11b promoter. CD11b‐DTR mice were made hypertensive by subcutaneous Ang II infusion. Two weeks later, the mice received intracerebroventricular infusion of either DT or saline. Blood pressure was monitored by tailcuff. It showed that systolic blood pressure reached ~140 mmHg in both groups by 2 wk. Microglial depletion caused a gradual reduction in blood pressure (20 mmHg) by the end of 4 wk. To validate the importance of microglia in neuroinflammation associated with hypertension, the expression of pro‐inflammatory cytokines in paraventricular nucleus (PVN) were analyzed by quantative RT‐PCR. Microglial depletion reduced the expression of both IL‐1β and TNFα in the PVN of hypertensive mice. Moreover, the norepinephrine levels in the kidney were significantly decreased in the microglia‐depleted mice vs. controls. These data strongly support our hypothesis that in hypertension, microglia play an importance role in initiating neuroinflammation and in sustaining blood pressure.Grant Funding Source: AHA and UCLA CTSI
Visualizing lymph movement in anuran amphibians with computed tomography (879.9)
Authors: Hedrick Michael , Hansen Kasper , Wang Tobias , Thygesen Jesper , Pedersen Michael 
Published: June 2021

Lymph flux rates in anuran amphibians are high relative to other vertebrates owing to ‘leaky’ capillaries and a very high interstitial compliance. Lymph movement is accomplished primarily by specialized lymph muscles and lung ventilation that move lymph through interconnected lymph sacs to the dorsally‐located lymph hearts which are responsible for pumping lymph back into the circulatory system. The highly compartmentalized lymph sacs have been described anatomically, but it is unclear how lymph moves through the lymphatic system to the lymph hearts. We used computed tomography (CT) to visualize an iodinated contrast solution, injected into various lymph sacs, through the lymph system in awake cane toads (Rhinella marina). Toads were anesthetized with MS‐222 and small bore cannulae (PE 50) were placed into a variety of lymph sacs(subvertebral, lateral, interfemoral, brachial, crural) to inject contrast solution (0.25‐1.0 ml; VisipaqueTM 320 mg I/ml). Isotropic 0.216 mm3/voxel CT scans were acquired with a 64‐Slice Siemens Somatom Definition (Siemens Medical Solutions, Germany) at 80 kV, tube current 273 mA. Scanning time was approximately 12 seconds and scans were performed repeatedly for 1 min to 180 min following injection of the contrast solution. CT‐data was analyzed qualitatively in the 3D viewer in Osirix‐software where movement of the contrast was clearly visible over time, although clearance rates differed considerably between lymph sacs. We observed vertical movement of contrast in lateral and interfemoral sacs as predicted from previous studies. A surprising result was the observation of a previously undescribed pathway for lymph movement from the subvertebral sac ventrally between the lungs. These visual results confirm predictions about the movement of lymph, but also provide some novel findings regarding the pathways for lymph movement.Grant Funding Source: Supported by the National Science Foundation and the Danish Research Council