bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subcutaneous white adipose tissue expression of HuR mediates cardiac pathology via adipose tissue-derived extracellular vesicles
Authors: Desarapu Rohan , Anthony Sarah , Guarnieri Adrienne , Parkins Sharon , Kuhnell Damaris , Langevin Scott , Tranter Michael 
Published: May 2023

Obesity is a rapidly growing epidemic worldwide, especially in the United States, and is associated with cardiovascular disease (CVD), diabetes, cancer, and a multitude of other comorbidities. Adipose tissue has been shown to act as an endocrine organ in the body and to mediate cardiac physiology. We have previously shown that deletion of HuR specifically in adipocytes (Adipo-HuR KO) induces cardiac fibrosis in mice, independent of traditional adipose/obesity co-morbidities (dyslipidemia, hypertension, diabetes).​ Deletion of HuR in the adipocyte affects both brown adipose tissue (BAT) depots as well as subcutaneous white adipose tissue (scWAT) depots. We have shown that HuR deletion in BAT (using a UCP1-driven cre model) maintains normal cardiac function compared to Adipo-HuR KO mice. This points toward scWAT being the primary mediator of cardiac pathology from adipose tissue, which is consistent with our previously published bioinformatic analysis suggesting HuR-dependent adipose tissue-derived extracellular vesicles (Ad-EVs) as the mechanism by which this occurs.The goal of this work is to identify the mechanisms by which HuR expression in subcutaneous white adipose tissue (scWAT) mediates cardiac function via Ad-EVs. Here, we show that Ad-EVs isolated from scWAT depots of our Adipo-HuR KO model induce significant hypertrophic signaling in vitro, compared to wild-type littermates. We also show that expression of HuR in scWAT specifically is decreased with obesity and age, suggesting a potential mechanistic link between obesity, HuR expression in scWAT, and CVD.In conclusion, our results demonstrate that loss of HuR expression in scWAT is sufficient to induce cardiac hypertrophy and fibrosis, in part through endocrine-mediated Ad-EV signaling. In addition, we are beginning to identify HuR-dependent gene expression patterns in human scWAT which may potentially play a significant role in this signaling axis. This work was supported by NIH grants R01-HL132111 and HL158671 (MT). RD is supported by a Peter Lauf Travel Award from the Ohio Physiological Society. SP is supported by an NIH Training grant T32HL125204 (PIs: Molkentin and Kranias). ARG was supported by American Heart Association Predoctoral Fellowship (916812). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
TRPV4 expression in the renal tubule is necessary for maintaining whole body K+ homeostasis
Authors: Stavniichuk Anna , Pyrshev Kyrylo , Zaika Oleg , Tomilin Viktor , Pochynyuk Oleh 
Published: May 2023

Distal segments of the renal tubule have a major role in controlling whole body K+ homeostasis by performing flow-induced K+ secretion (FIKS) during K+ load and K+ reabsorption in response to systemic K+ deficiency. The transient receptor potential vanilloid type 4 (TRPV4) Ca2+-permeable channel serves as the sensor of tubular flow thus being well-suited to govern K+ transport in the distal renal tubule. In the current manuscript, we directly tested whether TRPV4 function in the renal tubule is significant in affecting K+ balance. For this, we employed balance metabolic cage studies and systemic measurements with different K+ feeding regimens: high (5% K+), regular (0.9% K+), and low (<0.01% K+) in newly created transgenic mice with selective TRPV4 deletion in the renal tubule (TRPV4fl/fl-Pax8Cre) and their littermate genetic controls (TRPV4fl/fl). Successful deletion was verified by the absence of TRPV4 protein expression in renal homogenates and the lack of TRPV4-mediated Ca2+ influx in freshly-isolated split-opened collecting ducts. There were no differences in plasma electrolytes, baseline urinary volume, and K+ levels when both strains were fed regular K+ intake. In contrast, plasma K+ levels were significantly elevated in TRPV4fl/fl-Pax8Cre mice on both high and low K+ intake. This was associated with a marked decrease in 24 h urinary K+ levels in the knockout, whereas urinary volume and aldosterone levels were indistinguishable from the control TRPV4fl/fl littermates suggesting a direct decrease in the distal tubule K+ transport. Interestingly, we also detected significant differences in urinary pH levels indicative of the altered K+ reabsorption via H+-K+ ATPase in the collecting duct. Indeed, we detected a significantly faster pHi recovery after intracellular acidification with ammonium pulse in both acid secreting A- and base-secreting B-types of intercalated cells and to a lesser degree in principal cells in split-opened collecting ducts from TRPV4fl/fl-Pax8Cre mice on low but not regular K+ intake, which is consistent with augmented H+-K+ ATPase activity and K+ reabsorption in the knockouts. In summary, our results demonstrate an indispensable pro-kaliuretic role of TRPV4 in the renal tubule in controlling K+ balance and urinary K+ excretion during variations in dietary K+ intake This research was supported by NIH-NIDDK DK117865, DK119170, AHA EIA35260097 (to O. Pochynyuk) and AHA-19CDA34660148 (to V. N. Tomilin). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Postnatal Inhibition of TrkB Kinase Reduces the Number of Phrenic Motor Neurons
Authors: Brandenburg Joline , Fogarty Matthew , Zhan Wen-Zhi , Sieck Gary 
Published: May 2023

During embryonic development, the number of phrenic motor neurons (PhMNs) declines precipitously during the final trimester and continues into the early postnatal period. When BDNF/TrkB signaling is absent in utero, animals do not survive after birth, most likely due to excessive loss of vital motor neurons (e.g., PhMNs). Far less is known about the early postnatal effect of BDNF/TrkB signaling. We have shown that BDNF/TrkB signaling is important in promoting PhMN neuroplasticity in mature rodents. Taken together, we hypothesized that inhibition of BDNF/TrkB signaling during early postnatal development results in fewer PhMNs. Chemo-genetic TrkBF616A mutant mice were used to induce inhibition of TrkB kinase activity in response to oral administration (via drinking water) of a phosphoprotein phosphatase 1 inhibitor derivative (1NMPP1). 1NMPP1-induced TrkB kinase inhibition was initiated at P0 and continued until P21 and compared to untreated control mice. At P28, PhMNs were retrogradely labeled via rhodamine phrenic nerve dip. One day later, mice were euthanized, perfused with 4% paraformaldehyde, and the cervical spinal cord was excised and processed for longitudinal cryosectioning (70 μm). Labeled PhMNs were imaged by 3D high resolution confocal microscopy. The number of PhMNs were counted. PhMN somal surface area and number of primary dendrites were also determined. 1NMPP1-induced inhibition of TrkB kinase resulted in 24% fewer PhMNs (P=0.01) and 21% more primary dendrites (P=0.0002) than control mice. The distribution of PhMN somal surface areas was not affected. We conclude that BDNF/TrkB signaling is essential in promoting survival of PhMNs in the early postnatal period. BDNF/TrkB signaling during postnatal development also plays a role in paring primary dendrites. While inhibition of TrkB kinase did not significantly alter the distribution of PhMN somal surface areas at P28, it is possible that further growth of PhMNs into maturity might have been altered as larger PhMNs emerge as a result of disproportionate growth beyond this age in mice. Supported by National Institutes of Health grants R01-AG044615 (GCS), R01-HL96750 (GCS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effects of wetted inner clothing on heat strain while wearing ventilation garments in hot-dry and warm-humid environments
Authors: Tokizawa Ken 
Published: May 2023

The present study examined 1) the effect of wearing a water-soaked inner t-shirt with a ventilation garment on heat strain in undertaking moderate-intensity exercise (metabolic rate: 200 W/m2) in heat (37 °C, 50% RH, 2.8 kPa) in study 1, and 2) whether the cooling was effective in hot-dry (40 °C, 30% RH, 2.2 kPa) and warm-humid (32 °C, 80% RH, 3.8 kPa) environments in study 2. It was hypothesized that 1) wearing a water-soaked t-shirt in combination with a ventilation garment would attenuate heat and cardiovascular strain compared with a dry t-shirt/ventilation garment combination; and 2) mitigation of heat and cardiovascular strain would be greater in the warm-humid condition.In the study 1, while intermittent walking in the heat for 60 min, eight male subjects wore a dry inner t-shirt without fanning of a ventilation jacket as a control (CON). Meanwhile, under a fanned ventilation jacket, the subject wore a dry inner t-shirt (DRY) or an inner t-shirt soaked with 350 mL of tap water (WET). Increases in rectal temperature in the WET trial (0.7 ± 0.2 °C) were lower than in the CON (1.3 ± 0.3 °C) and DRY (1.1 ± 0.2 °C) (both p<0.05) trials. Heart rate and sweat loss were lowest in the WET, followed by DRY, and then CON (all p<0.05).In the study 2, the attenuation in elevation of rectal temperature, heart rate, and sweat loss in WET was observed in both hot-dry and warm-humid environments. There was no difference in the attenuation between the hot-dry and warm-humid conditions.These findings demonstrate that wearing a water-soaked inner t-shirt while using a ventilation garment is an effective and practical cooling strategy to mitigate heat strain during moderate-intensity exercise in hot occupations. Public (The project research of National Institute of Occupational Safety and Health, Japan) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Contribution of the tachykinergic receptors of the respiratory parafacial region on breathing activity
Authors: Maia Octávio , Oliveira Luiz , Takakura Ana , Moreira Thiago 
Published: May 2023

Ventilation is a process initiated in the central nervous system, essential for maintaining the body’s homeostasis, especially to regulate O2 and CO2 levels in blood and tissues. Based on functional and anatomical characteristics, the respiratory parafacial region was subdivided into two distinct populations, the ventral (pFV) and lateral (pFL) parafacial regions. Evidence suggests that both regions express high levels tachykinergic receptors and have an impact on breathing. However, little is known about the tachykinergic modulation of the tachykinergic signaling to control breathing output. In the present study, we pharmacologically investigated the respiratory effects elicited by the injection of substance P (SP) within the parafacial region as well as the role of NK1 receptors in the baseline and in the ventilatory response to hypercapnia (7% CO2). External intercostal muscle activity (IntEMG) was recorded in urethane-anesthetized male or female adult C57Bl6J mice. SP injections (1 μM - 30 nL) in the pFV elicited a significant increase in the IntEMG frequency (18.3 ± 5.3, vs. saline: -1.2 ± 0.8%), IntEMG amplitude (38.3 ± 11.6 vs. saline: -1.95 ± 2.5%) and IntEMG minute volume (62.4 ± 12.4 vs. saline: -3.1 ± 2.7%). In contrast, SP injections in the pFL elicited a significant reduction in the IntEMG frequency (-18.4 ± 4.5, vs. saline: -0.42 ± 0.42%) and an increase in the IntEMG amplitude (43.7 ± 15.2 vs. saline: 1.8 ± 1.8%). Bilateral blockade of NK1 receptors (GR82334 - 100 mM - 30 nL) in the pFV region was able to reduce the increase in the IntEMG amplitude (13.4 ± 5.5, vs. saline: 58.1 ± 24.5%), IntEMG frequency (5.1 ± 5.1, vs. saline: 13.6 ± 10.3%,) and IntEMG minute volume (19 ± 8, vs. saline: 77.6 ± 27.1%) induced by hypercapnia and completely eliminate the excitatory effect elicited by SP. Our results suggest that tachycinergic signaling exerts different effects on respiratory rate depending on the site of injections in the parafacial region and NK1 receptors within the pFV region are involved in the hypercapnia ventilatory response. FAPESP, CNPq, CAPES-PROEX. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Breathing irregularities in spontaneously hypertensive neonate rats
Authors: Zoccal Daniel , Vieira Beatriz , Mendes Letícia , Leirão Isabela 
Published: May 2023

An excessive sympathetic drive is commonly observed in hypertensive patients and critically contributes to increasing arterial pressure levels. The quality of postnatal life can impact sympathetic control in adulthood. Spontaneously hypertensive (SH) rats, an experimental model of neurogenic hypertension, exhibit breathing irregularities in adult life. In this study, we investigated whether SH rats display breathing abnormalities after birth, which could be a risk factor for developing sympathetic overactivity. Using head-out plethysmography, we found that the neonate (P0-2, male and female) SH rats (n=9) exhibited lower minute ventilation than age-matched normotensive rats (NT, n=14; 816±177 vs 1261±189 ml/min/kg, P<0.05) under resting conditions, mainly due to reductions in respiratory frequency (93±15 vs 132±13 cpm, P<0.05). The reduced baseline ventilation in the SH group was accompanied by a greater prevalence of periods of apneas and respiratory irregularities (P<0.05). Under hypoxia conditions (10% O2, 10 min), SH and NT rats (n=9/each) mounted similar transient increases in minute ventilation during the initial period of exposure due to increments in tidal volume. In contrast, the respiratory frequency in the SH rats decreased progressively below baseline levels during hypoxia exposure (42% reduction, P<0.05), while it remained similar to pre-hypoxia values in the control group. In rhythmic in vitro preparations from neonate SH rats (n=2), we identified ectopic bursts in the hypoglossal activity and prolonged inspiratory-related bursts in the preBötzinger complex compared to preparations from NT rats (n=2). Our findings indicate that breathing irregularities in SH rats are present from birth and could be linked to dysfunctions in the inspiratory rhythm-generating network. Financial support: FAPESP, CNPq. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
AT1a receptor knockout selectively in renomedullary interstitial cells of the kidney lowers basal blood pressure, impairs urine concentration, and attenuates angiotensin II-induced hypertension in RMIC-Agtr1a-/- mice
Authors: Li Xiao , Hassan Rumana , Hao Chuan-Ming , Zhang Ming-Zhi , Harris Raymond , Zhuo Jia 
Published: May 2023

We previously reported that global deletion of angiotensin II (Ang II) AT1a receptors significantly lowered basal blood pressure and impaired urine concentration in mice. As we also demonstrated that renomedullary interstitial cells (RMICs) of the kidney expressed a high level of AT1 (AT1a) receptors, we hypothesized that AT1a receptors in RMICs may play an important physiological role in maintaining basal blood pressure and urine concentration homeostasis. To test the hypothesis, we generated a novel mouse model with deletion of AT1a receptors selectively in the RMICs of the kidney medulla using inducible Tenascin-C-CreER2/Agtr1af/f recombination approach (RMIC- Agtr1a-/- ) in the present study. Adult male wildtype (WT) and RMIC- Agtr1a-/- mice (n=10-18 per group) were phenotyped under basal conditions and treated with or without a slow pressor dose of Ang II infusion via an osmotic minipump (~500 μg/kg/day, i.p.) for 2 weeks to determine the roles of AT1a receptors in RMICs in maintaining basal blood pressure and urine concentration homeostasis and in the development of Ang II-induced hypertension. Under basal conditions, telemetry systolic blood pressure was significantly lower in adult male RMIC- Agtr1a-/- than WT mice (WT: 122 ± 4 mmHg vs. RMIC-Agtr1a-/-: 102 ± 3 mmHg, P<0.01). This hypotensive phenotype in RMIC- Agtr1a-/- mice was associated with significant decreases in 24 h urine output (WT: 1.56 ± 0.15 mL/24 h vs. RMIC- Agtr1a-/- : 0.98 ± 0.13 mL/24 h, P<0.01), urinary sodium (WT: 207.9 ± 7.3 μmol/24 h vs. RMIC- Agtr1a-/- : 145.2 ± 5.4 μmol/24 h, P<0.01), and potassium excretion (WT: 221.0 ± 6.7 μmol/24 h vs. RMIC-Agtr1a-/-: 160.8 ± 10.6 μmol/24 h, P<0.01), respectively. Moreover, urine osmolality was markedly decreased in RMIC- Agtr1a-/- mice even though 24 h urine output was lowered (WT: 1724 ± 335 mOsm/Kg H2O vs. RMIC- Agtr1a-/- : 1128 ± 102 mOsm/Kg H2O, P<0.01). In response to Ang II infusion, telemetry systolic blood pressure increased to 148 ± 5 mmHg in WT mice, but it increased only to 129 ± 8 mmHg in RMIC- Agtr1a-/- mice ( P<0.01). Furthermore, Ang II infusion for 2 weeks failed to alter urine osmolality in RMIC- Agtr1a-/- mice (1226 ± 110 mOsm/Kg H2O, n.s.). In conclusion, we demonstrated for the 1st time that AT1a receptors in RMICs of the kidney medulla play a key role in physiologically maintaining basal blood pressure homeostasis and urine concentration, as well as in the development of Ang II-induced hypertension. R01DK123144, R01DK067299, R01DK102429 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Intravenous injection of fentanyl in adult awake goats increases arterial blood pressure and reduces heart rate without affecting metabolic rate or temperature
Authors: Forster Hubert , Grams Kirstyn , Neumueller Suzanne , Buiter Nicole , Hilbert Grace , Pan Lawrence , Lewis Stephen , Hodges Matthew 
Published: May 2023

At high doses, synthetic opioids are thought to slow heart rate and reduce mean arterial blood pressures in humans and rodents and could create a life-threatening situation. Herein, we report dose-dependent effects of intravenous (IV) injection of fentanyl on systolic (SYS), diastolic (DIA), and mean (MAP) arterial blood pressure, heart rate (HR) metabolic rate and body temperatures in adult female goats (n=7). Variables were measured 30 min before, during and up to 90 min after IV injection of vehicle (saline) or 25, 50, 75, 100, and 125 mcg/kg fentanyl. Baseline averages for SYS, DIA, MAP was 102, 73, 83 mmHg, respectively, and HR was 84 beats/minute (bpm). There were no significant changes in these values over 90 minutes when saline was injected. Between 8 and 10 minutes after fentanyl injection, SYS, DIA, and MAP increased substantially from control by about 40, 25, and 30 mmHg, respectively. These increases did not appear dose independent, but by 90 minutes post-injection SYS, DIA, and MAP decreased toward control at the lowest dose (25 mcg/kg). The fentanyl induced arterial hypertension was partially compensated by a ~15 bpm decrease in heart rate which changed minimally between 10 and 90 minutes after fentanyl injection. The sustained increase in arterial blood pressure indicates a sustained excitatory effect of fentanyl consistent with the excitatory effect of fentanyl on tidal volume and respiratory muscle activity (see additional abstracts from our group). This excitatory effect is not due to changes in metabolic rate and/or body temperature as we found no consistent effect of fentanyl injections on these variables. This excitatory effect of fentanyl appears species-dependent as opioid agonists injected into rats and humans typically induces arterial hypotension. Species dependency of fentanyl may reflect species variation in effects of fentanyl on vagal nerve endings, brainstem control centers, and/or cardiac receptors (J. Car.Pharm, 1985), or alternatively may reflect differences in fentanyl metabolism whereby metabolites may have differential effects on blood pressure among these species. NIH DA050571 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Neuronostatin induces gluconeogenic enzyme expression and glucose release in hepatocytes
Authors: Mahmood Ammar , Grote Stephen , Kolar Grant , Samson Willis , Yosten Gina 
Published: May 2023

Hepatic glucose production (HGP) is regulated by a complex system of hormones, receptors, signaling mechanisms, glycolytic and gluconeogenic enzymes, and many overlapping transcription factors. The proteins involved in HGP are attractive targets for antidiabetic therapy, and thus it is critical to identify and characterize new targets within the regulation of HGP. We identified a novel peptide, neuronostatin (NST), encoded in the somatostatin preprohormone that exerts its effects in the central nervous system, the heart, and the pancreas. NST is produced in the delta cells of the pancreatic islets and plays an important role in maintaining glucose homeostasis through enhancing glucagon secretion from the α cell and reducing insulin release from the β cell. In male rats, a bolus injection of NST significantly increased blood glucose over 30 minutes after administration. Likewise, the peptide delayed glucose clearance and diminished the insulin response to hyperglycemia in a glucose tolerance test. Our group also identified the orphan GPCR, GPR107, as a cognate receptor for the peptide. GPR107 is expressed in numerous tissues, including the liver. In searching for the role of NST in hepatic physiology, we observed that hepatocellular carcinoma cell line HEPG2 expressed GPR107. Thus, we hypothesized that NST would elicit hepatic glucose production. We found that treatment of HEPG2 cells with NST significantly elevated cFos mRNA expression, indicating that HEPG2 cells respond to the peptide. In addition, NST induced expression of key gluconeogenic enzymes and enhanced glucose release in HepG2 cells. In vivo, antagonism of the glucagon receptor in rats did not attenuate elevated blood glucose levels in response to treatment of NST, supporting a direct, glucagon-independent action of NST on HGP. Thus, our results suggest that NST could play a physiologically relevant role in the liver and that GPR107 could be a potential new target to modulate HGP. National Institute of Health (NIH) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.