bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Bradykinin B1 Receptor Blockade on Angiotensin II‐Induced Cardiac and Aortic Remodeling
Authors: McCormick Brittney , Huot‐Marchand Julie‐Emilie , deBlois Denis , Hale Taben 
Published: November 2023

Angiotensin II (AngII) is a growth factor known to induce vascular and cardiac hypertrophy and fibrosis. AngII has been shown to regulate bradykinin B1 receptor (B1R) expression in the heart and aorta and we have recently shown that concomitant B1R antagonism could prevent AngII‐induced cardiac fibrosis. The present study investigated the impact of AngII and bradykinin B1R antagonism on blood pressure and left ventricular (LV) and aortic hypertrophy. Male Sprague‐Dawley rats were treated for 4 weeks with vehicle or AngII (200 ng/kg per min) in the presence or absence of the B1R antagonist R‐954 (400 μg/kg per day). In addition, bromodeoxyuridine (BrdU) was infused to assess cellular proliferation. At sacrifice, mean arterial pressure (MAP) was assessed via carotid artery cannulation in anesthetized rats. The LV and aorta were weighed, and the aortic and cardiomyocyte cross sectional area (CSA) were measured. Additionally, LV DNA content was determined and aortic cellular proliferation was assessed via immunohistochemistry to measure BrdU incorporation. Relative to vehicle, AngII increased MAP (59%), aortic cell proliferation (144%), and aortic CSA (34%), ‐ effects that were not offset by B1R antagonism. However, B1R antagonism did attenuate the AngII‐induced increase in aortic mass. Similarly, AngII increased LV hypertrophy (35%) and total DNA content (44%) relative to control, both of which were prevented by concomitant B1R antagonism. Cardiomyocyte CSA was not different across treatment groups. This study reveals tissue‐specific effects of bradykinin B1R antagonism. Although AngII induced significant remodeling in both the heart and aorta, concomitant B1R blockade only prevented cell accumulation and remodeling in the LV. Future studies will investigate the mechanism underlying this effect to further elucidate the role of the bradykinin B1R and its interaction with AngII in remodeling heart and aorta.Support or Funding InformationCanadian Male Sexual Health Council
CMT‐3, an anti‐inflammatory, non‐antibiotic tetracycline, attenuates AngII‐induced hypertension
Authors: Sharma Ravindra K , Santisteban Monica , Lobaton Gilberto O , Richards Elaine M , Raizada Mohan K 
Published: November 2023

BackgroundOur previous studies have established that activation of microglial cells and neuro‐inflammation in autonomic brain regions, particularly in the paraventricular nucleus (PVN) of the hypothalamus, plays a critical role in hypertension (HTN). This conclusion is primarily based on the evidence that the tetracycline antibiotic minocycline (Mino) inhibits microglial activation and attenuates HTN. Since Mino has both anti‐inflammatory and antibiotic properties, we sought to determine the property responsible for its antihypertensive effects using the chemically modified tetracycline‐3 (CMT‐3), that has no antibiotic activity.ObjectiveWe hypothesized that central administration of CMT‐3, would inhibit microglial activation, neuro‐inflammation and attenuate HTN.MethodsSix‐week‐old male SD rats (n=8–12/group) were implanted with telemetry transducers. Ten days after surgery, 2 osmotic minipumps were implanted to subcutaneously infuse AngII (200ng/kg/min,) or vehicle and intracerebroventricularly infuse CMT‐3 (3.5μg/hr) or vehicle. Mean arterial pressure (MAP) was recorded weekly; after 4 weeks of AngII treatment, spectral analysis of was performed for autonomic nerve activity and anti‐Iba1 immunostaining was carried out to quantitate activated microglia in the brain.ResultsCMT‐3 significantly attenuated the AngII‐induced increase in MAP both in light: (Con:102±3, CMT‐3:101±4, AngII:158±23, AngII+CMT‐3:125±20 mmHg) and dark cycles (Con:102±2, CMT‐3: 102±3, AngII: 174±20, AngII+CMT‐3:145±28 mmHg). The heart to body weight ratio was similarly decreased (Con:2.9±0.3, CMT‐3:2.9±0.1, AngII:3.9±0.4, AngII+CMT‐3:3.3±0.2 mg/g; p<0.05) with CMT‐3. CMT‐3 normalized AngII perturbed autonomic activity, as measured by LF/HF of SBP (Con:1.8±0.7, CMT‐3:2.0±1.6, AngII:5.4±4, AngII+CMT‐3:2.9±1.9; p<0.001)). Furthermore, AngII increased activated microglial cells ~2.5‐fold, predominantly in the PVN, and CMT‐3 significantly attenuated this increase (p<0.01).ConclusionThese data indicate that inhibition of neuro‐inflammation is key in correction of autonomic dysregulation and attenuation of HTN. They suggest that the anti‐inflammatory, rather than the antibiotic property, of Mino mediates these effects. Thus, CMT‐3 may be a better therapeutic candidate for neurogenic resistant hypertension in humans as it circumvents the problems associated with continuous antibiotic administration.Support or Funding InformationThis work is supported by NIH grant R01HL033610
The Effect of a Patent Foramen Ovale and Sex on the Hypercapnic Ventilatory Response
Authors: Hardin Alyssa M. , Boulet Lindsey M. , Davis James T. , Chang Alex J. , Foster Glen E. , Lovering Andrew T. 
Published: November 2023

A patent foramen ovale (PFO) is a right‐to‐left intracardiac shunt pathway present in approximately 35% of the general healthy population. Individuals with a PFO (PFO+) exhibit higher alveolar to arterial oxygen difference (AaDO2) values at rest than subjects without a PFO (PFO−), indicating that PFO+ subjects have a source of right‐to‐left shunt significant enough to decrease gas exchange efficiency at rest. Additionally, PFO+ subjects have blunted ventilatory acclimatization to hypoxia compared to PFO− subjects. While the presence of a PFO is known to influence hypoxic chemosensitivity, it has yet to be determined if the presence of a PFO has an effect on the hypercapnic ventilatory response (HCVR).Thirty subjects (15 female) matched for height, weight, sex and age participated in this study. Subjects completed two hypercapnic breathing trials in a randomized and balanced order, separated by ≥ 40 minutes of rest between trials. At the start of each trial, subjects began breathing room air until steady‐state values for end‐tidal oxygen and carbon dioxide (PETO2 and PETCO2) were established. PETO2 and PETCO2 were then controlled utilizing a dynamic end‐tidal forcing system (AirForce). During the hyperoxic hypercapnia (HH) trial, PETO2 was clamped at 250 mmHg and PETCO2 was increased in a stepwise fashion to target values of +3 mmHg, +6 mmHg and +9 mmHg of each subject's baseline PETCO2. Each stage consisted of a 90 second steady‐state data collection period after each increase. The procedure for the normoxic hypercapnia (NH) trial was identical to the HH trial except that PETO2 was clamped at the resting baseline value for each subject and PETCO2 increased as above. Hypercapnic ventilatory response (HCVR) was calculated as the change in minute ventilation (VE) divided by the change in PETCO2 (L/min/Torr CO2).PFO+ subjects demonstrated a blunted, significantly lower HCVR than PFO− subjects during both the HH (PFO−: 1.80 L/min/Torr CO2 ± 0.17, PFO+: 1.19 L/min/Torr CO2 ± 0.14, p < 0.05) and NH (PFO−: 1.79 L/min/Torr CO2 ± 0.23, PFO+: 1.24 L/min/Torr CO2 ± 0.26, p < 0.05) trials. These data suggest that PFO+ subjects have a blunted ventilatory response to acute exposure to hypercapnia. Within the subset of female subjects, PFO+ females had a significantly lower HCVR than PFO− females in the HH trial (PFO−: 1.85 L/min/Torr CO2 ± 0.27, PFO+: 1.06 L/min/Torr CO2 ± 0.13, p < 0.05) and NH trial (PFO−: 1.81 L/min/Torr CO2 ± 0.28, PFO+: 1.15 L/min/Torr CO2 ± 0.11, p < 0.05). However, no differences were observed between the male PFO+ and PFO− subjects in the HH (PFO−: 1.77 L/min/Torr CO2 ± 0.37, PFO+: 1.35 L/min/Torr CO2 ± 0.24, p > 0.05) or NH (PFO−: 1.76 L/min/Torr CO2 ± 0.24, PFO+: 1.33 L/min/Torr CO2 ± 0.28, p > 0.05) trials. These results suggest that female PFO+ subjects have a blunted HCVR compared to female PFO− subjects.
Mitochondrial development is impaired in hyperoxic rats and this may underpin the blunting of the acute hypoxic ventilatory response
Authors: Fayyad Tariq H , Rakoczy Ryan J , Hartpence Annah J , Wyatt Christopher N 
Published: November 2023

Carotid body (CB) responses to hypoxia are low at birth and increase over time to mature responses. Using an in vitro rat CB‐carotid sinus nerve (CSN) preparation, Kholwadwala and Donnelly (1992) demonstrated that the CSN activity in response to hypoxia increased from low levels to robust adult responses after two weeks. This time course of maturation was paralleled by an increase in TASK channel sensitivity to hypoxia in the O2‐sensing Type I cells (Kim et al, 2011). Previous studies have indicated that a fall in Type I cell mitochondrial volume and an increase in the rate of oxidative phosphorylation may underpin the development of the hypoxic ventilatory response (Paulet et al, 2012).Our most recent studies addressed the phenomenon that hyperoxia delays the maturation of the acute hypoxic response (Bavis, RW et al, 2010). Our initial findings suggest that hyperoxia caused the juvenile non‐oxygen‐sensing Type I cells to remain locked in a mitochondrial rich state and that as the rat developed this mitochondrial rich state impaired development of the hypoxic response. Thus there appears to be a correlation between mitochondrial volume and the ability to respond to hypoxia in rat Type I cells.Support or Funding InformationNIH RO1 HL091836
Phox2b‐negative Parafacial Neurons Simultaneously Regulate Active Expiration and Airway Patency Under Hypercapnia in in situ Preparations of Rats
Authors: Moraes Davi J.A. , de Britto Alan A. 
Published: November 2023

Hypercapnia produces active expiration in rats and the recruitment of late‐expiratory (late‐E) neurons located in the parafacial Respiratory Group (pFRG) of the ventral medullary brainstem. We tested the hypothesis that hypercapnia produces active expiration and concomitant cranial respiratory motor responses controlling the oropharyngeal and upper airway patency by pFRG late‐E neurons disinhibition, but not via synaptic excitation. Phrenic nerve, abdominal nerve (AbN), cranial respiratory motor nerves, subglottal pressure, and medullary and spinal neurons/motoneurons were recorded in in situ preparations of juvenile rats. Hypercapnia evoked AbN active expiration (n=12), exaggerated late‐E discharges in cranial respiratory motor outflows (n=12), and glottal dilatation (n=6) via late‐E synaptic excitation of abdominal (n=8), hypoglossal (n=6) and laryngeal (n=12) motoneurons. Simultaneous rhythmic late‐E activity in previously silent Phox2b‐negative pFRG neurons was also evoked by hypercapnia (n=12). In addition, hypercapnia‐evoked AbN active expiration, neural and neuronal late‐E activities were eliminated by pFRG inhibition (n=18), but not after blockade of synaptic excitation (n=9). On the other hand, pFRG inhibition did not affect either hypercapnia‐induced inspiratory increases in respiratory motor outflows (n=12) or CO2 sensitivity of the more medial Phox2b‐positive neurons in the retrotrapezoid nucleus (RTN; n=8), despite elimination of AbN active expiration. Our data suggest that neither RTN Phox2b‐positive nor other CO2‐sensitive brainstem neurons activate Phox2b‐negative pFRG late‐E neurons under hypercapnia to produce AbN active expiration and concomitant cranial motor respiratory responses controlling the oropharyngeal and upper airway patency. Hypercapnia seems to produce pFRG late‐E neuronal disinhibition in in situ preparations of juvenile rats to activate abdominal, hypoglossal and laryngeal motoneurons.Support or Funding InformationFAPESP: SÃO PAULO RESEARCH FOUNDATION
Mitochondrial Hsp90 exerts pro‐survival functions in Pulmonary Arterial Hypertension
Authors: BOUCHERAT Olivier , BREUILS‐BONNET Sandra , CHABOT Sophie , MELOCHE Jolyane , VITRY Géraldine , LAMBERT Caroline , NADEAU Valérie , TREMBLAY Eve , SUTENDRA Gopinath , MICHELAKIS Evangelos , CHAE Young , ALTIERI Dario , PAULIN Roxanne , PROVENCHER Steeve , BONNET Sébastien 
Published: November 2023

RATIONALEPulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and no therapeutic option. Although the causal pathomechanisms contributing to remodeling of the pulmonary vascular bed in PAH are still unclear, several features, including hyperproliferation and resistance to apoptosis of pulmonary smooth muscle cells (PASMCs) sustained by oncogenic pathways activation and metabolic alterations, have led to the emergence of the cancer‐like concept. The molecular chaperone heat shock protein 90 (Hsp90), by interacting with its client proteins, is directly associated with malignant growth and proliferation. In addition to be highly expressed in the cytosol, Hsp90 exists in a subcellular pool compartimentalized in the mitochondria (mtHsp90) of tumor cells, but not in normal cells, where it promotes cell survival.OBJECTIVEWe hypothesized that Hsp90 up‐regulation in PAH triggers PASMC proliferation and resistance to apoptosis.METHODS AND RESULTSWe showed that Hsp90 is up‐regulated in lungs and PASMCs isolated from distal pulmonary arteries from PAH patients compared to control donors. Using pharmacological inhibitors (AT13387 and 17‐AAG), we demonstrated that cytosolic Hsp90 stabilizes the expression of numerous clients proteins overexpressed in PAH that promote cell growth and survival. More importantly, we demonstrated that Hsp90 is specifically expressed in PAH‐PASMCs mitochondria (immunoblot, dual immunofluorescence and immunogold electronic microscopy), and not in healthy cells. Whereas cytosolic Hsp90 inhibition displays a lack of absolute specificity for PAH‐PASMCs, selective inhibition of mtHsp90 activity using Gamitrinib decreased PAH‐PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) without affecting control cells. In PAH‐PASMCs, mtHSP90 accumulation prevents the accumulation of mitochondrial DNA damage and maintains bioenergetics functions (Seahorse). In the fawn‐hooded rat and monocrotaline‐induced models of PAH, mtHsp90 inhibition reduces PA remodeling thus improving pulmonary hemodynamic parameters.CONCLUSIONWe demonstrated for the first time that accumulation of mtHsp90 is a cardinal feature of PAH‐PASMCs, contributing to the development of vascular lesions.Support or Funding InformationENTELLIGENCE young investigator program
α1G T‐type Ca2+ Channel Contributes to the Angiogenic Capacity of Pulmonary Microvascular Endothelial Cells
Authors: Zheng Zhen , Chen Hairu , Zhou Chun , Liu Bao , King Judy A , Alexeyev Mikhail F , Wu Songwei 
Published: November 2023

Pulmonary microvascular endothelial cells (PMVECs) characteristically possess intrinsic rapid proliferation and angiogenic capacity, both of which are essential for vascular homeostasis as well as tissue remodeling and repair in response to vascular injury. Although it has long been established that cellular Ca2+ signaling plays an important role in regulating cell proliferation and angiogenesis, the molecular mechanisms underlying such regulation remain poorly understood. In the present study, we demonstrated that α1G T‐type Ca2+ channel, the only voltage‐gated Ca2+ channel expressed in PMVECs, is critical for cell proliferation, adhesion, migration, and in vitro tube formation capability. PMVECs exhibited rigorous in vitro capillary sprout‐like, tube formation in a reconstituted basement membrane extracellular matrix (Matrigel). Pharmacological blockade of the T‐type Ca2+ channel with NNC 55‐0396, a highly selective T‐type channel blocker, dose‐dependently reduced the tube formation capacity, by 26% at 5 μmol/L and 48% at 10 μmol/L (P < 0.001). In stark contrast, pharmacological blockade of TRPC4 or TRPV4, two other Ca2+ permeable channels expressed in PMVECs, had no effect on tube formation. Similarly, α gene suppression by shRNA significantly reduced tube formation capacity compared to the scramble shRNA control. Next, cell proliferation assays revealed that the cell proliferation in PMVECs was significantly reduced by α1G gene suppression with shRNA. Further, pharmacological blockade of the T‐type Ca2+ channel with NNC 55‐0396 dose‐dependently reduced the number of adherent PMVECs in a Matrigel‐coated substratum, by 31% at 5 μmol/L and 66% at 10 μmol/L (P < 0.001). Moreover, pharmacological blockade of this channel attenuated cell migration as revealed by a wound‐healing assay in PMVECs. Taken together, these findings support a novel functional role of the site‐specific endothelial α1G T‐type Ca2+ channel in the control of cell angiogenic capacity in PMVECs.Support or Funding InformationSupported by HL66299
Reactive Oxygen Species Signaling in the Hypoxia‐Tolerant Turtle and Goldfish Stellate and Pyramidal Neurons Is Species Specific
Authors: Buck Les , Hossien‐Javaheri Nariman , Pillai Varshinie , Hawrysh Peter 
Published: November 2023

The majority of vertebrate species are not hypoxia‐tolerant; however, some freshwater turtles and fish from the carp family are tolerant of extreme hypoxia for days or months. Two examples are the western painted turtle and the goldfish which provide excellent models for the study of hypoxia‐tolerance mechanisms in brain. We have previously shown that severe hypoxia results in a natural decrease in reactive oxygen species (ROS) in turtle brain; therefore, here we investigate in a turtle brain sheet and goldfish brain slice model the response of pyramidal and stellate neurons to scavenging of ROS with MPG (N‐2‐mercaptopropionyl glycine) for comparison to the tissue exposed to severe hypoxia. Using single cell fluorescence we first confirm that ROS levels do indeed decrease with severe hypoxia in goldfish brain slices. Then using whole‐cell and perforated patch clamp techniques and ROS scavenging we find that whole cell conductance (Gw) increases from 4.5 to 6.6nS in both turtle cell types and from 3.96±0.95nS to 6.84±0.62nS in both goldfish cell types. In both cases the increased Gw is related to increased GABA‐A receptor conductance since application of the GABA‐A receptor inhibitor gabazine blocks the increase. While goldfish and turtle pyramidal cells remained mostly quiescent the action potential frequency (APf) of goldfish stellate neurons increased with ROS scavenging from 0.03±0.009Hz to 2.04±0.12Hz or 68 fold. Turtle stellate neurons exhibited a unique burst firing pattern where AP's are clustered into discrete bursts of about 2 AP's per burst with quiescent periods in between bursts. When exposed to ROS scavenging overall APf decreased from 0.49 ± 0.14 Hz to 0.33 ± 0.07 Hz but the number of AP's per burst increased from 2.4 ± 0.21 to 3.0 ± 0.12. With ROS scavenging the stellate neuron burst pattern coalesces into a burst every 7–8 s that corresponds with the frequency of giant inhibitory GABAergic current recorded from pyramidal neurons. It remains unclear how these differences in ROS signaling impacts the hypoxia‐tolerance of each species but we conclude that the unique responses of stellate neurons is species specific.Support or Funding InformationNatural Sciences and Engineering Council of Canada grant to LTB
Caffeine governs molecular mechanism(s) on circadian rhythm and circadian clock gene expression
Authors: Kang Hyunbon , Park Sookyoung , Jin Yunho , Hong Yonggeun 
Published: November 2023

Caffeine is one of the most widely used psychoactive substances, and it induces the arousal in the CNS, but also disrupts the quality of sleep. Recent studies reported that caffeine can affect the circadian rhythm, which associates many aspects of physiology, energy metabolism, sleep and homeostasis. Therefore we examined the arousal effects of caffeine via behavioral test, and determined its effects on circadian rhythm by measuring clock gene and clock‐controlled gene expression in mice brain. Male C57BL/6 mice were randomly divided into control, three experimental groups treated with vehicle, caffeine and caffeine with adenosine, respectively. Before administration of caffeine, forced treadmill exercise was applied to mice inducing physiological fatigue. Balance beam test and foot fault test were used to evaluate the balance ability in subjected mice. Caffeine treatment reduced weight gain, suggesting physiological effect of caffeine to inhibit food intake. In addition, average time to cross beam and error number of foot slip after caffeine injection were decreased compared with control. A foot fault was defined as the misplacement of fore or hind foot, thus the foot fault number after caffeine treatment was reduced compared with control. There were differences in expression of circadian clock genes including Clock, Per2, Cry1, and Cry2 by caffeine injection. Thus, these results demonstrate that caffeine can alter circadian rhythm in mice by regulating circadian clock gene expression.Support or Funding InformationNRF‐2013R1A2A2A01067169 to Y.H., NRF‐2014R1A1A3051724 to S.P., Republic of Korea.
Behavioral Profile Assessment in Offspring of Swiss Mice Underwent to Neonatal Treatment with Fluoxetine
Authors: da Silva Cortes Wellington , Laureano‐Melo Roberto , Conceição Rodrigo Rodrigues , Souza Janaina Sena , Lau Raphael Silva , da Silva Almeida Claudio , Giannocco Gisele 
Published: November 2023

Serotonin exerts an important role in the central nervous system embryogenesis of mammals, influencing directly several brain systems ontogeny. Therefore, we investigated the effect of neonatal Fluoxetine (FLU), a selective serotonin reuptake inhibitor, on the behavioral expression of adult male Swiss mice. For this purpose, three groups (n=6 each, and ~35g) of pregnant female Swiss mice were mated. The offspring obtained was treated with FLU (1mg/kg, s.c.) from the 5th at 15th post‐natal day. On the 16th post‐natal day, female puppies were euthanized and hippocampus was dissected for RNA analysis whereas the male offspring, by completing 70 days of life, were underwent a behavioral assessment in open field, light‐dark box and tail suspension test. Statistical analysis was performed by t‐Student and the means were considered significantly different when p<0.05. According to our results, the programmed animals had a decrease in TPH2 (0.07±0.007 vs. 1.07±0.19, p<0.001), 5HT1a (0.08±0.007 vs. 1.02±0.17, p<0.001), SERT (0.35±0.08 vs. 1.09±0.18, p=0.004), BDNF (0.19±0.02 vs. 1.07±0.19, p=0.001) and LMX1B (0.03±0.01 vs. 1.12±0.25, p=0.001) expression. In addition, it was observed less immobility time in tail suspension test (77.6±7.25 vs. 112.1±12.2, p=0.02) and higher grooming time in open field test (7.6±1.4 vs. 3.1±0.9, p=0.01). In light‐dark box test, the animals treated with FLU showed a shorter time in the light side than control (36.69±10.4 vs. 76.2±5.48, p<0.01). These findings suggest that programming with FLU during the neonatal period alters hippocampal serotonergic system, promoting anxiety and depression‐like behaviors in adults.Support or Funding InformationFAPERJ & CNPq