bluuebunny/crossref_metadata_2025_split huggingface dataset:
An orthostatic load of 1/4G and 1/3G differentially activates vascular and cardiac components of cardiopulmonary reflexes
Authors: Jain Mansi , Chandran Dinu , Jaryal Ashok , Deepak Kishore 
Published: May 2023

Introduction – Orthostatic load of varying degree affects cardiopulmonary reflexes and baroreflex. Cardiopulmonary reflexes initiate even before the baroreflex activation in response to volume changes in body caused by changed G load. The cardiopulmonary reflex has two effector components i.e., Heart and Vasculature. Lower body negative pressure (LBNP) is a non-invasive tool used to study the physiological effects of varying G loads. Aim & Objective - The study was designed to explore the varying orthostatic load triggering cardiopulmonary reflexes. Material & Methods - 33 healthy human volunteers were recruited. Continuous heart rate and blood pressure – Systolic, diastolic and mean blood pressure (measured as the area under curve of the pulse waveform) were recorded. Orthostatic load of 1/4G and 1/3G were chosen in order to prevent fall in blood pressure and baroreflex activation. The measurements were taken in supine resting state (0 mmHg), at -10 mmHg (1/4 G) and -15 mmHg (1/3G). Heart rate variability was calculated from the Lead II ECG with the help of Labchart Pro 8 ® software. Peripheral vascular resistance (PVR) was estimated indirectly from arterial pressure waveform. Statistical analysis was performed using Graphpad Prism. Results – At 1/4G of orthostatic load (-10 mmHg of oscillatory LBNP) activation of vascular component (PVR) of cardiopulmonary reflex was found with no changes in the cardiac component (HRV). At 1/3G of orthostatic load (-15 mmHg of oscillatory LBNP), there were activation of the cardiac component (LF:HRV, LF/HF:HRV) associated with further increase in the vascular component (PVR). Conclusion – Data suggests that 1/3G and 1/4G orthostatic load applied using LBNP despite no change in blood pressure, causes differential activation of vasculature and cardiac effector components of cardiopulmonary reflexes No funding received for carrying out the study 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.
The effect of inhaled 7% CO2 on salivary cortisol and amylase in Behaviorally Inhibited and Non-Behaviorally Inhibited Humans
Authors: Harshberger Mary , Apostoli Giana , Ehlert Luke , Wolf Olivia , Wiseman Connor , Martino Paul , Miller Daniel , Miller Justin , Terrill Sarah , Allen Michael , Hodges Matthew 
Published: May 2023

Behavioral inhibition (BI) is believed to be a genetically determined temperament characteristic that affects roughly 33% of the human population. These individuals are associated with a higher vulnerability to stressful stimuli compared to non-behaviorally inhibited (NBI) individuals. Our previous study demonstrated that BI individuals experienced decreased heart rate variability (HRV) compared to NBI individuals. Our study suggested that female BI individuals have significantly lower parasympathetic nervous system (PNS) activity, however, it is unknown how BI affects perceived stress. In order to better understand behavioral inhibition in humans, our laboratory explored salivary cortisol and amylase levels in response to stressful stimuli of breathing-enhanced CO2 (carbon dioxide). We hypothesized that BI individuals have a greater increase in both salivary cortisol and amylase after exposure to a stressful stimulus when compared to NBI individuals. Prior to the experiment, participants completed AMBI and RMBI forms. These forms indicate BI tendencies to participants, where AMBI is scored out of 32, where 15.5 is the threshold for BI tendencies, and RMBI is scored out of 36, 11.5 being the threshold. Salivary samples were taken at the beginning and end of the study. They were set up on a breathing apparatus and began to breathe room air for a 15 minute control period. Following this, participants either continued to breathe room air as the control group or were given 7% CO2, and then exposed to room air again. Overall, there was no difference in salivary cortisol and amylase between NBI and BI subjects following the onset of 7% CO2. Our data suggests that 7% CO2 may be too much of a respiratory stressor to reveal any physiological differences between the two groups. Ongoing studies will evaluate cortisol and amylase output after the CO2 dose response curve. 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.
Non-biased RNA-Seq Analysis of Cardiac Tissues post Acute Lung Injury
Authors: Xia Zhiqiu , Zucker Irving , Lisco Steven , Wang Han-Jun 
Published: May 2023

Patients suffering from acute lung injury (ALI) are at a high risk of developing cardiac arrhythmias. Our recent study demonstrated that bleomycin (Bleo)-induced ALI in rats exhibited significantly more spontaneous premature ventricular contractions (PVCs) from one to three weeks post induction. Although spontaneous PVCs disappeared at 4 weeks post ALI, PVCs were evoked again by electrical stimulation of the decentralized stellate ganglia in Bleo-exposed rats but not in normal rats. In the current study, we aimed to utilize non-biased RNA-Seq analysis to identify potential gene candidates in cardiac tissues, which may be associated with cardiac arrhythmia during the recovery from ALI. We created an ALI rat model using a single tracheal instillation of bleomycin (2.5 mg/kg), with saline as a vehicle (Veh) control. Blood troponin level was measured between Veh- and Bleo-treated rats at Week 1 (W1) post Veh/Bleo. Cardiac tissues were harvested at W4 post Veh/Bleo for RNA-seq analysis and following PCR validation. At W1 post ALI, cardiac troponin level was significantly increased in Bleo-treated rats whereas it was undetectable in Veh-treated (Control) rats. RNA-seq analysis indicated 11 downregulated (AABR07045427, Habp2, AC130862, Per2, Coch, Phactr3, Angptl7, LOC103690108, Mthfd2, Sorcs1, U6) and 13 upregulated (Calhm5, Metazoa_SRP, Tgm1, Pcare, Drd4, Selplg, AABR07027722; Rn5-8s, 5_8S_rRNA) genes in cardiac tissues at 4 weeks post ALI vs Veh. PCR validated that the gene expressions of Habp2, Coch, Phactr3, LOC103690108, Mthfd2 were significantly downregulated and the gene expressions of Pcare, Drd4 were significantly upregulated in the hearts of Bleo-treated rats at W4 post ALI. Our study demonstrated that multiple gene changes in cardiac tissues are associated with cardiac injury and arrhythmogenesis in bleomycin-induced ALI in male rats. Future studies will further determine the cause-effect relationship between these altered genes and cardiac arrhythmia post ALI. This study was supported by NIH grant R01 HL-152160 and in part, by NIH grants R01 HL126796. 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.
Studies on the Mechanism of Lactate-Induced Increase in Ca2+ Oscillations in Carotid Body Type 1 Cells
Authors: Shun Justin , Kang Dawon , Kim Donghee 
Published: May 2023

Blood lactate concentration under normal conditions is ~1 mM and increases during hypoxia and exercise due to elevated anaerobic metabolism. Recent studies suggest that lactate acts directly on carotid body Type 1 chemoreceptor (CB) cells and elevates cytosolic [Ca2+], which increases transmitter secretion from CB cells, carotid sinus afferent nerve activity and ventilation. The mechanism by which lactate increases [Ca2+] is still uncertain. Chang et al (2015) reported that lactate binds to Gs-coupled receptor (OlfR78 in rat/mice) whose signaling leads to a rise in [Ca2+]. Torres-Torrelo et al (2021) reported that lactate enters the cell via the monocarboxylate transporter and increases the ratio of NADH to NAD+, which opens cation channels to cause cell depolarization and Ca2+ influx. Another potential mechanism is that lactate itself inhibits K+ channels and/or activates non-selective cation channels to depolarize CB cells and increase Ca2+ influx. Here we studied the effects of lactate on ion channels, cell Em and Ca2+ oscillations in CB cells. Ion channel and Em studies: Sodium lactate (10 mM, pH 7.4) produced a mild depolarization (<10 mV) in ~30% of CB cells. In HEK cells expressing TASK-1/3, lactate (10 mM) caused mild inhibition of the whole-cell current and cell depolarization (as detected by Fluovolt fluorescence). Lactate activated a 20-pS Ca2+-sensitive monovalent cation channel (CaMCC) in ~50% of CB cells. [Ca2+] oscillations: Lactate (1-20 mM) increased the frequency of Ca2+ oscillations in CB cells (and thus averaged [Ca2+]), and this effect was blunted by removal of extracellular Ca2+, nifedipine and 2-APB. Forskolin that elevated cytosolic [cAMP] had no effect on Ca2+ oscillations, and H-89 (PKA inhibitor) did not block lactate- and hypoxia-induced increase in Ca2+ oscillations. Summary: Our studies do not support the OlfR78-Gs-cAMP signaling pathway in lactate-induced increase in Ca2+ oscillations and [Ca2+] in CB cells. Our study supports a mechanism in which lactate activates CaMCC, possibly initiated by inhibition of TASK and/or other signals, to cause cell depolarization that increases Ca2+ influx and the frequency of Ca2+ oscillations. NIH and Rosalind Franklin University of Medicine and Science 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.
Role of the median preoptic nucleus in the development of chronic DOCA-salt hypertension
Authors: Collister John , Fritcher Nora , Nahey David 
Published: May 2023

Lesions of the anteroventral third ventricle (AV3V region) are known to prevent many forms of experimental hypertension, including mineralocorticoid (DOCA-salt) hypertension in the rat. However, AV3V lesions include the organum vasculosum of the lamina terminalis (OVLT), portions of the median preoptic nucleus (MnPO), as well as efferent fibers from the subfornical organ (SFO), thereby limiting the ability to define the individual contribution of these structures to the prevention of experimental hypertension. We have previously reported that the SFO does not contribute to the chronic hypertensive response to DOCA-salt in rats, and yet the OVLT plays a significant role in the development of DOCA-salt hypertension. Since efferent fibers of the OVLT project to and through the MnPO, the present study was designed to test the hypothesis that the MnPO is necessary for DOCA-salt hypertension in the rat. Male Sprague-Dawley rats underwent unilateral nephrectomy followed by a week of recovery, and subsequent SHAM (n=5) or electrolytic lesion of the MnPO (MnPOx; n=7). Throughout another week of recovery and during the experimental protocol, rats consumed a 2% NaCl diet and 0.9% NaCl drinking solution. 24-hour mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). No differences in the 5-day average control MAP were observed between groups (MnPOx: 104 ± 1 mmHg; SHAM: 107±2 mmHg). The chronic pressor response to DOCA was attenuated in MnPOx rats by day 11 of treatment and continued such that MAP increased 25±3 mmHg in SHAM rats by day 21 of DOCA compared to 14±3 mmHg in MnPOx rats. These results support the hypothesis that the MnPO is an important brain site of action for the pathogenesis of DOCA-salt hypertension in the rat. University of Minnesota Grant In Aid #546839 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.
Butyrate ameliorates Paneth cell defects, total inflammation, and epithelial cell apoptosis during mitochondrial dysfunction driven by Prohibitin 1-deficiency
Authors: Alula Kibrom , Dowdell Alexander , Lee Scott , Colgan Sean , Theiss Arianne 
Published: May 2023

Introduction: Prohibitin 1 (PHB1) is a mitochondrial chaperone protein important for maximal activity of the electron transport chain. PHB1 deficiency in intestinal epithelial cells (IECs) or specifically in Paneth cells (PCs) induces epithelial mitochondrial dysfunction, PC defects, gut microbiota dysbiosis, and spontaneous ileitis in mice by 20 weeks-of-age. Dysbiotic gut microbiota has been implicated in inflammatory bowel diseases and is associated with the decreased abundance of short chain fatty acids (SCFAs; acetate, propionate, and butyrate)-producing bacteria. SCFAs play a significant role in reducing intestinal inflammation and enhancing epithelial barrier dysfunction. We tested the hypothesis that luminal SCFA levels were decreased in mice with PHB1 deficiency and that supplementation of SCFAs will ameliorate intestinal inflammation during mitochondrial dysfunction driven by loss of PHB1. Methods: Ileal luminal contents were collected from Phb1fl/fl (control) and Phb1iΔIEC (Phb1-deficient in IECs) mice at 20 weeks of age and SCFAs were measured by gas chromatography-mass spectrometry. Phb1iΔIEC and Phb1fl/fl littermate mice were treated with 20 mM butyrate dissolved in their drinking water from 16 to 20 weeks-of-age and PC defects were measured by antimicrobial peptide expression (Lysozyme, Cryptdin 3, Cryptdin 5, and Ang4) and Lysozyme staining allocation into secretory granules. Ileitis was measured by histological scoring and pro-inflammatory cytokine expression. To test epithelial intrinsic responses, ileal crypt enteroids derived from Phb1iΔIEC and Phb1fl/fl littermate mice were treated with 200 μg/ml healthy ileal stool lysates (from Phb1fl/fl mice) or dysbiotic stool lysates (from Phb1iΔIEC mice) for 16 hours with or without 0.05 mM butyrate, 0.5 mM propionate, 0.5 mM acetate, alone or in combination. Enteroid viability and apoptosis were measured by morphological change and cleaved Caspase 3 expression. Results: Butyrate was significantly decreased in ileal stool of Phb1iΔIEC mice. Butyrate supplementation in Phb1iΔIEC mice protected against ileitis and PC defects. Dysbiotic stool lysate decreased viability and increased apoptosis in Phb1-deficient enteroids that were prevented by butyrate supplementation. Conclusion: Mitochondrial health in IECs cells is crucial for healthy gut microbiota composition and for epithelial defense when the microbiome becomes dysbiotic. Butyrate rescues IECs from insults caused by dysbiotic gut microbiota during mitochondrial dysfunction driven by PHB1 deletion. Funding: APS Postdoctoral Fellowship 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.
The loss of hepatic PPARα prompts fatty liver disease-induced hypertension and cardiovascular disease
Authors: Badmus Olufunto , Kipp Zachary Kipp , Bates Evelyn , da Silva Alexandre , Taylor Lucy , Martinez Genesee , Hinds Terry , Stec David 
Published: May 2023

Non-alcoholic fatty liver disease (NAFLD) often clusters with obesity, diabetes, and hyperlipidemia. For unknown reasons, the leading cause of death in patients with NAFLD is cardiovascular disease (CVD). Most preclinical models of NAFLD are induced by high-fat diet feeding that induces obesity and glucose intolerance, each provoking CVD independent of changes in hepatic fat. To determine the role of NAFLD in the promotion of CVD, independent of changes in body weight and insulin sensitivity, we utilized our hepatocyte-specific PPARα knockout ( Ppara HepKO ) and littermate control ( Ppara fl / fl ) mice. After 30 weeks on a standard diet, male Ppara HepKO mice exhibited elevated hepatic fat content compared to littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, p<0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01mM, p<0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The Ppara HepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, p<0.05), impaired diastolic function, and adverse cardiac remodeling consisting of dilated cardiomyopathy. The mice with the loss of hepatic PPARα displayed alterations in vascular stiffness, including increased pulsatility index, resistive index, and intima-media thickness in the abdominal aorta and carotid artery, which was corroborated with reduced kinase signaling in the aortas of the Ppara HepKO mice. Our findings indicate that hepatic PPARα is vital in protecting the cardiovascular system via a liver-specific mechanism. Also, the  Ppara HepKO mice are possibly a novel model for studying NAFLD-induced CVD. This work was supported by National Institute of Health R01DK126884, and the National Heart, Lung and Blood Institute P01 HL05197-11 (D.E.S) and the National Institute of General Medical Sciences P20GM104357-02. 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.
Understanding myocardial contractility comprehensively through multiple dimensions
Authors: Geloian Gorune , Kuang Serena 
Published: May 2023

Myocardial contractility (MC) is commonly defined in a vague matter as the intrinsic contractile property of cardiac muscle, or its ability to generate force and shorten. This understanding is insufficient. In this abstract, we propose that MC should be comprehensively conceptualized through multiple dimensions, (i.e., it is not merely intrinsic and it is more than an ability) through logical analysis as follows. First, when conceptualizing MC in medical physiology, it is no doubt that force (F) and velocity (V) of muscle shortening are two aspects of the muscle’s ability. Both F and V are dependent on afterload, an extrinsic factor. This extrinsic factor-dependency indicates the following: 1) muscle contraction exhibits adaptability, i.e., muscles are intelligent when interacting with extrinsic factors and only produce F and/or V appropriate to the given extrinsic factor(s); and 2) what is intrinsic is not ability (F and/or V), but capacity (including FC and VC) which is truly independent of extrinsic factors. An ability is always a fraction of capacity and a result of adaptability; capacity (FC and VC, although not quantifiable so far, but theoretically present) is the ultimate source of ability (F and V) which can be experimentally quantified. Second, it is well known that F is determined by at least two aspects: a component (F_FS) governed by the Frank-Starling Law (i.e., the force-length relationship) and a component (F_Ca) by the level of intracellular Ca2+ transient during cross bridge cycles that determines the actual number of cross-bridges binding to thin filaments. A gap in current medical physiology education is that when introducing muscle physiology, the Frank-Starling law that determines F_FS is always introduced, but when presenting MC specifically, quite often, the contribution of F_FS to F is ignored and only F_Ca (i.e., inotropism) is included. Finally, V can also be at least subdivided into the rate of Ca2+ releasing into the cytoplasm (V_Ca) from the sarcoplasmic reticulum as well as the rate of ATP hydrolysis catalyzed by the myosin heads (V_ATP). In conclusion, MC is a complex concept, which needs to be described through multiple dimensions including but not limited to its capacity, adaptability, and ability. The capacity can be further differentiated into Fc and Vc, and ability into F and V, both of which having at least two subdimensions, respectively: F_FS and F_Ca; V_Ca, and V_ATP. 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.
UBR1 Mediates ACE2 Ubiquitination and Hypertension in Male Mice
Authors: Elgazzaz Mona , Nuzzo Anna , Restivo Luke , Miao Kevin , Lazartigues Eric 
Published: May 2023

Angiotensin-II is one of the main players in the renin angiotensin system (RAS). It mediates vasoconstriction and inflammation through binding to angiotensin-II receptor 1 (AT1R). Conversely, angiotensin converting enzyme 2 (ACE2) counteracts the vasopressor effect of Ang-II/AT1R by converting Ang-II to Ang (1-7). We previously reported that in hypertension, Ang-II mediates ACE2 internalization and ubiquitination. Recently, we identified UBR1, an E3 ubiquitin protein ligase, as a potential ubiquitinase modulating ACE2 expression. While UBR1 deletion has been linked to impaired neurogenesis and cardiovascular development, there is no study that has assessed the role of UBR1 in cardiovascular regulation. Here, we aimed to investigate the role of UBR1 in hypertension. C57BI/6J mice (3-month-old, M=8, F=6) were implanted with subcutaneous osmotic pumps containing Ang-II (600 ng/kg/min) for 4 weeks and BP monitored by telemetry. UBR1 protein expression was upregulated in the hypothalamus of hypertensive male mice but not in females (Mean ±SEM: 3.3 ±0.6 vs.1.1 ±0.1; fold change to GAPDH; p<0.05) while ACE2 was reduced (1.5 ±0.2 vs. 4.1 ±0.3; p<0.05). In vitro, human aortic endothelial cells (HAEC) treated with Ang-II (100 nM) also showed an increase in UBR1 protein expression compared to vehicle (72.5 ±3.4 vs. 39.4 ±3.4 fold change to tubulin; p<0.05) and a parallel reduction in ACE2 (3.5 ±0.1 vs. 25.2 ±1.7; p<0.05). Conversely, HAEC treated with UBR1 siRNA and Ang-II exhibited a reversal of Ang-II-induced ACE2 downregulation (42.6 ±1.2 vs. 3.5 ±0.1 p<0.05). To further confirm the role of UBR1 in mediating hypertension, C57BI/6J male mice (3-month-old, n=10/group) were injected with either UBR1 small hairpin RNA (shRNA) or scrambled shRNA bilaterally in the paraventricular nucleus of the hypothalamus. After 4 weeks, BP was recorded before and 2 weeks after Ang-II infusion, as above. Baseline mean arterial pressure (MAP) was not different in UBR1 shRNA-treated mice compared to controls (MAP: 102.7 ±4.1 vs. 108.4 ±2.3 mmHg). Interestingly, UBR1 shRNA-treated mice showed a blunted Ang-II mediated hypertension compared to scramble shRNA group (MAP: 131.7 ±3.7 vs. 146.3±5.1 mmHg, student t test, p<0.05) suggesting that UBR1 plays a critical role in neurogenic hypertension. In summary, hypertension is associated with upregulation of UBR1 and a parallel downregulation of ACE2, while knockdown of UBR1 resulted in reduced hypertension to Ang-II infusion. We conclude that UBR1 upregulation in hypertension might contribute to ACE2 ubiquitination and a reduction of its compensatory activity. NHLBI HL150592- Veterans Affairs Merit Award BX004294 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.