bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Metformin on Cardiometabolic risk factors in Polycystic Ovary Syndrome: Comparison between races
Authors: Chatakondi Raksha , Salau Faridah , Pruett Jacob , Romero Damien , Yanes-Cardozo Licy
Published: May 2023

Purpose: Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in reproductive-age women, is characterized by androgen excess and ovarian dysfunction. PCOS women have an increased prevalence of metabolic syndrome components, such as an increased blood pressure (BP), insulin resistance (IR), and obesity. Metformin is the most frequently prescribed insulin sensitizer in women with PCOS. Recent evidence suggests that Black Women (BW) with PCOS have an increased incidence of cardiometabolic (CM) risk factors compared to their White Women (WW) counterparts. It is unclear if metformin has a different effect in BW versus WW with PCOS. Thus, the aim of the current study is to elucidate whether the effect of metformin on CM risk factors is different between BW with PCOS and WW with PCOS at the University of Mississippi Medical Center (UMMC). Hypothesis: CM risk factors will be more pronounced in BW with PCOS compared to WW with PCOS. There will be no difference in the impact of metformin on CM risk factors when comparing BW with PCOS to WW with PCOS. Methods Used: UMMC de-identified patient data from 2013-2022 were obtained from electronic medical records (EMR) using UMMC's Research Data Warehouse. The ICD-10 code of PCOS, E28.2, and code for Type 2 Diabetes Mellitus (T2DM), E11.9, were used to filter patients and encounters. Metformin users were then identified. CM risk factors were analyzed and compared between BW and WW with PCOS. Data are expressed as averages and statistical analysis was performed using SPSS, with p <0.05 considered significant. Summary of Results: From 2013 to 2022, EMRs of 3,260 PCOS patients were analyzed. Of these, 322 patients were co-diagnosed with T2DM. A total of 169 patients were identified as metformin users. BW with PCOS were younger than WW with PCOS (27 yo versus 34 yo). Compared to WW with PCOS, BW women with PCOS have significantly higher body mass index (45.5 vs. 41.16, p<0.001). There was no difference in BP between groups. The rate of current or former smoking doubled in WW with PCOS compared to BW with PCOS. BW with PCOS presented with an HbA1c of 7.5% whereas WW with PCOS presented with an HbA1c of 7.1%. Conclusions: BW with PCOS on metformin have a significantly higher body mass index than WW with PCOS. In contrast, former and current smoking status was more prevalent in WW with PCOS. Race/ethnicity plays a significant role in the CM risk factors in women with PCOS. Implementing strategies to ameliorate cardiovascular diseases in women with PCOS should consider the impact of race in clinical manifestations.

No external funding sources

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.
Does hyperoxia stimulate breathing?
Authors: Huggard Joshua , Guluzade Nasimi , Duffin James , Keir Daniel
Published: May 2023

Hyperoxia has been shown to stimulate ventilation (V̇E) in a dose-dependent manner. Whether this occurs due to an oxygen (O2)-specific mechanism or secondary to carbon dioxide (CO2) retention at the central chemoreceptors (via the Haldane effect) remains unclear. This study measured the ventilatory response to isoxic-hyperoxic CO2 modified rebreathing (an estimate of central chemoreflex sensitivity) with O2 clamped at increasingly higher hyperoxic pressures. We hypothesized that the slope of the V̇E versus PCO2 relationship is fixed and independent of hyperoxic severity. Fourteen healthy participants (6 females; mean ± SD age: 25 ±7 years) visited the laboratory on four occasions to perform three repetitions of modified rebreathing in four isoxic-hyperoxic conditions: “mild”: PO2=150 mmHg; “moderate”: PO2=200 mmHg; “high”: PO2=300 mmHg; and “extreme”: PO2=700 mmHg. The level of isoxic-hyperoxic PO2 was randomized between visits. Throughout rebreathing, breath-by-breath V̇E, end-tidal PCO2 (PETCO2) and O2 (PETO2) were measured by pneumotach and dual gas analyser. For each trial, the PETCO2 at which V̇E began to rise was identified as the ventilatory recruitment threshold (VRT, mmHg). The V̇E data prior to VRT provided baseline V̇E (V̇Ebsl, L∙min-1) and the slope of the linear response above VRT estimated central respiratory chemoreflex sensitivity (V̇ES, L∙min-1∙mmHg-1). For each hyperoxic condition, VRT, V̇Ebsl, and V̇ES from like-trials were averaged and between condition comparisons were assessed by repeated measures analysis of variance. There was no effect of PETO2 on V̇Ebsl (mild: 6.7±3.4 L∙min-1; moderate: 5.9±3.0 L∙min-1; heavy: 5.5±1.6 L∙min-1; extreme: 6.1±3.2 L∙min-1; p=0.35), VRT (mild: 42.7±3.2 mmHg; moderate: 42.0±2.2 mmHg; heavy: 42.2 ±2.4 mmHg; extreme: 41.5±2.4 mmHg; p=0.17) or V̇ES (mild: 5.04±2.78 L∙min-1∙mmHg-1; moderate: 4.64±1.90 L∙min-1∙mmHg-1; heavy: 4.68±1.92 L∙min-1∙mmHg-1; extreme: 4.49±1.72 L∙min-1∙mmHg-1; p=0.47). The hyperoxic V̇E versus PCO2 relationship was unaltered across a range of PO2 spanning mild to extreme. These data indicate that hyperoxia is not an independent stimulant of breathing.

Supported by NSERC

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.
Blood pressure responses by fitness status following a physical activity intervention in sedentary adults
Authors: Leicht Zachary , Weeldreyer Nathan , Adams Marc , Angadi Siddhartha
Published: May 2023

Background: Blood pressure and peak oxygen uptake (VO2peak) are strong independent predictors of all-cause and cardiovascular mortality. A VO2peak of 8 METs or greater is associated with greater cardiovascular health and probability of survival, whereas individuals with a VO2peak less than 8 METs are at greater risk for cardiovascular and all-cause mortality. Increasing physical activity in insufficiently active adults is associated with improvements in blood pressure (BP). Additionally, the relationship between an individual’s baseline VO2peak and BP responses following a walking intervention are unknown. Therefore, we examined the change in BP in individuals stratified based on baseline VO2peak (< 8 METs & ≥ 8 METs). We hypothesized that those with a VO2peak < 8 METs would see greater blood pressure responses compared to those with a VO2peak ≥ 8 METs. Methods: Cross-sectional, secondary analyses were carried out on data from a previously conducted clinical trial that included insufficiently active (as determined by accelerometry) individuals (N=518). Subjects underwent BP measurements, anthropometric testing, and a treadmill-based VO2peak test with ventilatory gas exchange assessment to determine VO2peak. Subjects with missing data were excluded from analyses. Additionally, only valid VO2peak tests (≥90% age-predicted HRmax, RER > 1.0) were included. Three hundred and sixty nine individuals had BP measured and met the criteria for a valid VO2peak test. Subjects were then stratified based on baseline VO2peak: low fit (<8 METS), and high fit (≥8 METS). Linear mixed model analyses were carried out to examine main effects (time and VO2peak category) of the walking intervention on BP. The interaction of time and VO2peak category was examined as well. Data are presented as means ± SD with α set at 0.05. Results: Eighty-one individuals had a VO2peak greater than or equal to 8 METs (age = 41.9±10.0 years; BMI = 28.8±4.8; VO2peak = 31.1±3.1 mL/kg/min; Males/Females = 55/26). Two-hundred and eighty-eight individuals had a VO2peak less than 8 METs (age = 45.9±8.6 years; BMI = 34.4±6.5; VO2peak = 22.4±3.2 mL/kg/min; Males/Females = 75/213). There was a significant group by time interaction effect for changes in systolic BP (≥ 8 METs: Pre = 120.8±1.4, Post = 123.0±1.6 mmHg, < 8 METs: Pre = 122.1±0.7, Post = 120.4±1.0 mmHg) (p = 0.03). There was no significant effects found for DBP. Conclusions: These secondary analyses found that SBP significantly decreased following a 6-month walking intervention in individuals with low-fitness. These data suggest that those with lower baseline CRF are likely to have greater declines in SBP.

Supported by NIH R01CA1989

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 Phosphodiesterase-9A inhibitor PF04447943 improves coronary microvascular rarefaction via Peroxiredoxin-5 in the ZSF1 rat model of HFpEF
Authors: Fopiano Katie Anne , Pearson William , Buncha Vadym , Lang Liwei , Hamdani Nazha , Bagi Zsolt
Published: May 2023

Coronary microvascular dysfunction contributes to the development of left ventricular (LV) diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF), a prevalent symptom that has limited targeted treatment options. Selective pharmacological inhibitors of phosphodiesterase 9A (PDE9A), such as PF04447943, have emerged as a potential therapeutic approach for the treatment of cardiometabolic diseases, in part, owing to their antioxidant effects. We hypothesized that PDE9A inhibition has beneficial effects on the coronary microvasculature, thereby improving LV diastolic function in HFpEF. In order to study this, the Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat, a model of human HFpEF, was employed in which it was found that progressively developing coronary microvascular rarefaction, as quantified by an unbiased, three-dimensional reconstruction of the coronary microvascular network (Vesselucida360), as well as vasodilator coronary arteriole dysfunction are associated with the development of LV diastolic dysfunction, which were improved by the treatment with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks). These coronary microvascular changes were accompanied by an increase in cardiac 3-nitrotyrosine, a marker of nitrosative stress, which was also mitigated by PF04447943 treatment. Furthermore, mass spectrometry-based proteomics and pathway analyses identified peroxiredoxin-5 (PRDX5) as one of the predominantly downregulated antioxidants in the heart of the obese ZSF1 rats, which was augmented after PDE9A inhibition. From this data, it was concluded that PDE9A inhibition, potentially through augmenting the PRDX-5 antioxidant mechanism, improved coronary vascular rarefaction and vasodilator function, thereby restoring LV diastolic function in obese ZSF1 rats.

T32HL155011

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.
Using synaptic connections to dissect neural microcircuitry
Authors: Clark John , Horn Madison , Farrell Evan , Dang Alice , Quiroga Liliana , Williams Cole , Valadez Jullian , Beaudoin Gerard
Published: May 2023

There are a number of methods used to study synapses through selective labeling and control. However, these techniques are often cytotoxic, difficult to implement, or lack the selectivity required to most effectively study microcircuits. We aim to create two novel techniques for studying how the brain is wired – a method for transsynaptic genetic labeling and a method for selectively destroying synapses. For synaptic labeling we are using the C. elegans orthologs for the Notch-Delta signaling system, Glp-1 and Lag-2. Glp-1 was modified by replacing the intracellular portion of the protein with cre recombinase, a site directed DNA recombination enzyme. It is hypothesized that when a cell expressing the chimeric Glp1-Cre protein comes in close contact with a cell expressing Lag-2, cre recombinase will be released allowing for the selective expression of a fluorescent molecule based on cell proximity. In vitro testing via confocal microscopy indicates that the labeling mechanism performs as expected, labeling cells based on contact in HEK 293T cells.To selectively destroy synapses, we have developed a chimeric protein, CadPlexin, that will activate repulsion signals through homophilic binding between two cells connected by a synapse. CadPlexin is composed of the extracellular domain of fruit fly DE-Cadherin and the transmembrane and intracellular domains of mouse plexin-B2. Cadherins bind to one another homophillically, acting to bind cells with one another. Plexins, when dimerized and activated by their usual ligand, Semaphorin, will cause a downstream signaling cascade that induces cell-cell repulsion. We hypothesize that, when two cells expressing CadPlexin are in close contact (i.e. at a synapse), CadPlexin will selectively destroy the synapse, as the extracellular domains from DE-Cadherin will bind together and mimic semaphorin binding and clustering required to activate plexin signaling. Preliminary results from in vitro experiments suggest that CadPlexin performs as expected, seen through stress fibers in the actin cytoskeleton of Cos7 cells transfected with CadPlexin – a characteristic cytoskeletal change induced through Plexin signaling. Together, these techniques will allow us to label synaptically connected neurons and destroy synapses with surgical precision.

Funding Sources: Murchison Summer Research Fellowship, Trinity University Start-Up Funds, McNair Scholars Program, the Brain and Behavior Research Foundation NARSAD Young Investigator Award, Mary E. Groff Foundation, Women in STEM Program.

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.
Electronic cigarettes exposures modulate Heart Rate and Heart Rate Variability
Authors: Castellanos Jocelyn , Cornett Carson , Luna Karla , Li Liqiao , Gonzalez David , Middlekauff Holly , Gupta Rajat , Jordan Maria , Ruenger Dennis , Zhu Yifang , Shao Xuesi , Roos Kenneth , Araujo Jesus
Published: May 2023

Background: Despite a lack of empirical data, an unprecedented rise in electronic cigarettes (ECs) has been widely perceived as safe. Multiple studies support a causal link between tobacco cigarette (TC) use and cardiovascular (CV) diseases; however, there is a lack of data with EC use. We have previously shown that chronic and acute EC use decreases heart rate variability (HRV) in humans, likely via increased sympathetic nervous system activation. Objective: We aimed to evaluate HRV effects induced by brief EC exposures utilizing an in-vivo model for freely moving C57BL/6 mice. Methods and Results: Telemetry devices were implanted in the abdomen of six 10-week-old C57BL/6 male mice to monitor electrocardiographic activity continuously. Mice underwent an exposure protocol designed to reflect human vaping topography with two EC exposures, each lasting 15-minutes (4-sec puff/ 26-sec Air) followed by 45-min post-exposure periods. Air (primary control) and PBS (secondary control) were also included, each with their own post-exposure events. During EC exposures, we observed bradycardic effects in heart rate (HR) with the standard deviation of NN intervals (SDNN), root mean square of successive differences (RMSSD), and the proportion of adjacent normalized RR intervals that differed by more than 6 ms (pNN6) significantly (p< 0.05) altered as compared to Air exposures. After EC exposures, SDNN, RMSSD and pNN6 parameters significantly decreased compared to Air. No significant differences between Air and PBS were observed in these parameters. Frequency domain parameters also indicated significant changes in HRV; the low frequency (LF) and high frequency (HF) bands showed marked increases during and after the EC exposures, while the log (LF/HF) ratio remained relatively unchanged, suggesting a possible coactivation of both parasympathetic and sympathetic branches of the autonomic nervous system. Conclusion: Short-term EC exposures lower heart rate and altered HRV in mice in an acute manner, suggesting that ECs may not be safe as previously assumed.

This work was funded by the Tobacco-Related Disease Research Program (TRDRP) which included the High Impact Pilot Research Award [28IP-0036], the Cornelius Hopper Diversity Award Supplement and the Student Research Award Supplement, the UCLA Center for Occupational and Environmental Health (COEH) Student Project Award, and in part by the National Institute of Environmental Health Sciences (NIEHS) via the Student-to-Scientist Bridge program at California State University, Northridge [5R25ES025507].

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.
Expression of human sPRR in renal collecting duct cells increases blood pressure in female mice independently of its circulating levels
Authors: Arthur Gertrude , Poupeau Audrey , Nichols Kellea , Osborn Jeffrey , Hinds Terry , Loria Analia
Published: May 2023

Elevated circulating sPRR has been associated with essential hypertension, obesity-related hypertension, heart failure and chronic kidney disease in humans. However, the exact contribution of tissue-specific human sPRR in blood pressure control remains to be investigated. Therefore, we evaluated the effect of human sPRR on circulating sPRR and blood pressure control when expressed in mouse kidney, adipose tissue or liver from both male and female mice.Human sPRR-Myc-tag transgenic mice were bred with mice expressing either Hoxb7/Cre, Adiponectin/Cre or Albumin/Cre to selectively express human sPRR (HsPRR) in the collecting duct of the kidney (Kid-HsPRR), adipose tissue (Adi-HsPRR) or liver (Liv-HsPRR), respectively. The presence of human sPRR-Myc-tag (28 KDa) was validated in each mouse model by detecting the presence of C-myc. HsPRR and control (WT) male and female mice were fed a control diet throughout the study (n=8-12/group). At 6 months, baseline and acute blood pressure responses were assessed by radio-telemetry.Tissue expression of sPRR increased in kidney-derived HsPRR (M: 1.0±0.2 vs. 1.6±0.3 AU, F: 1.0±0.1 vs. 1.7±0.2 AU p<0.05), adipose-derived HsPRR (M: 1.0±0.3 vs. 4.7±1.5 AU, F: 1.0±0.2 vs. 3.2±1.4 AU p<0.05) and liver-derived HsPRR mice (M: 1.0±0.2 vs. 9.7±0.8 AU, F: 1.0±0.1 vs. 8.7±0.9 AU p<0.05) but only liver-derived HsPRR mice elevated circulating sPRR (M: 7.0±2.4 vs. 125.0±7.9 ng/ml, F: 2.2±0.4 vs. 93.9±13.4 ng/ml p<0.05). Human sPRR increased blood pressure only in female mice expressing HsPRR in kidney (F: 111±2 vs. 121±4 mmHg p<0.05). Also, only female mice expressing HsPRR in kidney displayed a blunted acute response to losartan injection (M: -30.1±3.3 vs. -22.1±3.7, F: -16.3±2.4 vs. 14.1±5.8 Δ mmHg p<0.05) and Ang II-induced pressor response in acute (M: 28.9±5.1 vs. 47.6±4.4 mmHg p<0.05, F: 35.2±7.2 vs. 26.9±7.5 mmHg) and chronic fashion (M: 33.9±3.6 vs. 30.7±5.0, F: 35.1±6.8 vs.17.6±3.2 Δ mmHg, p<0.05).Overall, our data show that increased intrarenal human sPRR expression contributes to increase blood pressure in a sex-specific manner. Taken together, increased HsPRR in kidney is associated with hypertension and impaired response to AT1R blockade and AngII-induced pressor response suggesting a dysfunctional AT1R-mediated signaling that could be due to ligand competition.

These studies were supported by grants from the American Heart Association (13SDG17230008), the National Institute of General Medical Sciences (P30 GM127211), the Center for Clinical and Translational Sciences (UL1TR000117) and the National Heart Lung and Blood Institute (R01HL142969-01)

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.
Potential role of UCP-1 for mediating beneficial effects of exercise in an endometriosis rat model
Authors: Torres James , Cruz Myrella , Appleyard Caroline , Chompré Gladys
Published: May 2023

Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue in areas outside the uterus. Previous studies in our laboratory demonstrated that endometriosis animals have increased mesenteric adipose tissue (MAT), inflammation, and implanted endometrial vesicles, which are all decreased by voluntary exercise. Interestingly, the levels of Uncoupling Protein 1 (UCP-1), a mitochondrial protein, are known to be increased by exercise promoting thermogenesis, and decreasing inflammation in rodents. However, the possible role of UCP-1 in endometriosis is still unclear. Our aim was to study the effects of exercise on UCP-1 in MAT near the endometrial implants in an endometriosis rat model. Hypothesis: UCP-1 increases due to exercise decreasing the MAT and thus beneficially impacts the endometrial vesicles. Methods: Endometriosis was induced by implanting uterine tissue on the intestinal mesentery in young adult female Sprague Dawley rats where the control group only received sutures. Exercise rats had access to a running wheel after induction: ENDO-EX or SHAM-EX, while non-exercised animals didn’t (ENDO and SHAM; n=10=11/group). After sixty days of intervention, animals were sacrificed and UCP-1 immunofluorescent staining was performed on collected MAT near the vesicles (ENDO, n=3; ENDO-EX, n=3; SHAM, n=4; SHAM-EX, n=4). Results: The vesicles from ENDO-EX animals had significantly decreased average weight (p<0.05) and smaller average total area (p<0.01) compared with the ENDO group. UCP-1 staining shows a trend to increase in exercise groups when compared to non-exercise groups. Interestingly, there is a moderate negative correlation between UCP-1 expression and vesicle size (r=-.69). Conclusions: Exercise is related to increasing the UCP-1 pathways in MAT that may be associated with decreasing the size of the endometrial vesicle implants.

Supported by R15AT009915 and HRD-2008186.

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.
Impact of Plant-Derived Dietary Fibers on Energy and Glucose Homeostasis
Authors: Howard Elizabeth , Meyer Rachel , Weninger Savanna , Kangath Archana , Duca Frank
Published: May 2023

The gut microbiota contributes to the development of metabolic disease, and it is well known that diet shapes the gut microbiota, emphasizing the need to better understand how diet impacts metabolic disease via alterations in the gut microbiota. Dietary fiber intake is linked with improvements in metabolic homeostasis in humans, and specific fibers beneficially alter the gut microbiota, promote weight loss, and improve glucose homeostasis. In a previous study, we found that specific plant-based flours, including wheat and barley, supplemented into a high-fat diet (HFD) reduced body weight and adiposity and improved glucose tolerance in rats. However, whether this was due to specific fibers within the flours remains unknown. To test the impact of various dietary fibers on energy and glucose homeostasis, we supplemented HFD-fed mice with 5 different fibers (beta-pectin, beta-glucan, wheat dextrin, resistant starch, or cellulose as a control) at 10% (w/w) for 18 weeks (n=12/group), measuring body weight, adiposity, indirect calorimetry, and glucose tolerance. We found that only beta-glucan supplementation in a HFD decreased adiposity and body weight gain and improved oral glucose tolerance compared to HFD with cellulose, while all other dietary fibers failed to improve metabolic homeostasis. Supplementation with beta-glucan increased energy expenditure and locomotor activity in mice compared to HFD-cellulose. Despite a lack of metabolic effect for most dietary fibers, all fibers supplemented into a HFD shifted the cecal microbiota composition and exhibited increased SCFA levels. However, only beta-glucan supplemented mice specifically exhibited an increase in Ileibacterium relative abundance, as well as higher cecal butyrate levels compared to HFD-cellulose. These findings demonstrate that beta-glucan is a promising therapeutic option for diet-induced obesity and glucose tolerance, possibly via increased energy expenditure. Future studies will investigate the role of the gut microbiota and butyrate in the metabolic improvements observed with beta-glucan supplementation in HFD-feeding.

USDA National Institute of Food and Agriculture

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.
ADAM17 overexpression improves cerebrovascular vasoreactivity and cognitive function in the APP/PS1 mouse model of Alzheimer's disease
Authors: Fopiano Katie Anne , Tian Yanna , Suggs Hayden , Buncha Vadym , Lang Liwei , Wang Rongrong , Filosa Jessica , Bagi Zsolt
Published: May 2023

The disintegrin and metalloproteinase 17 (ADAM17) exhibits α-secretase activity, whereby it can prevent the production of neurotoxic amyloid precursor protein-α (APP). ADAM17 is abundantly expressed in vascular endothelial cells and may act to regulate vascular homeostatic responses, including vascular growth and vasomotor function. We hypothesized that cerebrovascular ADAM17 plays a role in the pathogenesis of Alzheimer’s disease (AD). Here we found that 8-10 months old APP/PS1 mice (expressing transgenes for APP Swedish mutation and PSEN1 with L166P mutation) with significant cognitive deficits display a markedly reduced expression of ADAM17 in cerebral microvessels. Systemic delivery and AAV-mediated re-expression of ADAM17 in APP/PS1 mice improved cognitive functioning, without affecting β-amyloid plaque density. Moreover, we found that the endothelium-dependent vasodilator function of isolated and pressurized cerebral arteries in APP/PS1 mice was impaired, which was restored to normal levels by the ADAM17 re-expression. The cerebral microvascular network density in the APP/PS1 mice before or after ADAM17 re-expression was not affected. In addition, proteomic analysis identified several differentially expressed molecules involved in AD neurodegeneration and repair that were reversed by ADAM17 re-expression. Thus, we propose that a reduced ADAM17 expression in cerebral microvessels impairs vasodilator function, whereby it contributes to the development of cognitive dysfunction in APP/PS1 mice, and that ADAM17 can potentially be targeted for therapeutic intervention in AD.

T32HL155011; 20PRE35211126

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.
Glucocorticoid Receptor-beta (GRb) is a driver of adiposity via PPARgamma in adipose tissue: Lessons learned from the first CRISPR GRb KO animals
Authors: Martinez Genesee , Kipp Zachary , Stec David , Hinds Terry
Published: May 2023

Obesity and its associated comorbidities are major contributors to deaths worldwide. This has led to increasing rates of multiple obesity-associated comorbidities, such as type II diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. A conundrum exists in that short-term glucocorticoid therapy reduces body weight, but the long-term chronic treatment causes weight gain and adiposity. Because of these effects observed clinically, we are interested in better understanding the complex role of glucocorticoid receptor (GR) isoforms in lipid and glucose metabolism. We hypothesized that the conundrum is related to an imbalance of the GRα and GRβ isoforms. They arise from a single GR gene ( Nr3c1) due to the alternative splicing of exon 9 and are antagonists to one another. To test this hypothesis, we developed specialized GRβ CRISPR knockout (KO) technology to target GRβ for KO in mice, and these animals only express the GRα isoform. The GRβ homozygous knockout (KO) mice seem to be lethal. However, the heterozygous KO (GRβHetKO) mice are viable, with no observable phenotypes on standard chow. Therefore, we used GRβHetKO mice to study the effects of this isoform on adiposity. We placed the GRβHetKO and GRβWT mice on a high-fat diet (HFD) for 8 weeks. We found that the GRβHetKO mice fed HFD had significantly reduced body weights (p-value <0.05) and adiposity (p-value <0.01) compared to their littermates, which was paralleled with significantly reduced PPARγ (p-value <0.01) expression in inguinal white adipose tissue (iWAT) but not in eWAT or liver tissues. The liver histology sections showed decreased lipid accumulation. Molecular analysis of GRβ-PPARγ signaling indicates that GRβ positively affects PPARγ transcriptional activity. We conclude that GRβ drives PPARγ expression and activity in adipose to induce adiposity in iWAT, which might affect fat accumulation in the liver. Our studies here indicate that future studies of GRβ might explain differences observed in the clinic for short- and long-term glucocorticoid therapies, and a better understanding of the GR isoforms could benefit patients with obesity and possibly improve obesity-associated comorbidities.

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.
Distinct effects of cell-free hemoglobin on oxygen pressure dynamics of fast vs. slow twitch muscle
Authors: Lemke Aviv , Calvo Nainoa , Hirai Daniel , Ferguson Scott
Published: May 2023

Hemolysis occurs following exposure to environmental stressors (e.g., microgravity) and in hemolytic diseases (e.g., sickle cell disease). When released from the red blood cell, cell-free hemoglobin (Hb) reduces nitric oxide (NO) availability and impacts skeletal muscle microvascular oxygen pressure (PO2 mv) dynamics during contractions in mixed fiber type muscle. However, the impact of cell-free Hb on fast- vs. slow twitch muscles remains unknown. Thus, the purpose of this investigation was to test the hypothesis that cell free Hb would lower the PO2 mv in slow, but not fast, twitch muscle. Phosphorescence quenching was used on two groups of young-adult male Sprague-Dawley rats to measure PO2 mv of the gastrocnemius (n=10) and soleus (n=8) muscles. Measurements were made at rest and during 180 s of 1-Hz contractions (6-8 v) under control conditions and following 50 mg of Hb infusion (tail-artery catheter). Mean arterial pressure (MAP) was monitored via a femoral artery catheter. Cell-free Hb increased MAP by 48% in the gastrocnemius and soleus groups (gastrocnemius, control: 93 ± 14, Hb: 138 ± 15; soleus, control: 89 ± 10, Hb: 132 mmHg, p<0.01 for both). Hb resulted in a shorter time delay (control: 10.29 ± 6.38, Hb: 3.88 ± 3.06 s) and faster mean response time (control: 22.03 ± 5.82, Hb: 14.29 ± 4.18 s) at the onset of contractions for the gastrocnemius (p<0.05 for both). There were no significant Hb induced differences in any kinetic parameter in the soleus (p>0.05 for all). Contrary to our original hypothesis and despite significant increases in MAP, cell-free Hb did not alter the kinetic response or the contracting steady-state PO2 mv in the slow-twitch soleus muscle. However, the kinetic response during the crucial rest-exercise transition in the gastrocnemius was significantly faster following Hb infusion, suggesting that Hb disrupts QO2/VO2 matching in fast-twitch muscle. Given the ~48% greater MAP following Hb infusion, these results suggest that cell-free Hb may disrupt skeletal muscle vascular conductance during contractions but may not impact PO2 mv in a fiber-type specific manner.

Robert C. Perry fund of the Hawai'i Community Foundation 21ADVC-109518 and NIH-L60HL134123

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.
Early program seminar to promote learning physiology via a core concepts approach
Authors: Sweeney Terrence , Sweeney Terrence
Published: May 2023

Spurred by the foundational work of Michaels, McFarland, Modell and others 1,2 in establishing and promoting a consensus collection of core concepts in physiology that facilitate learning, an increasingly broad collection of physiology educators have begun to embrace the employment of a core concepts approach to teaching and learning physiology. That said, challenges remain in the classroom in convincing students to forego the siloed and highly specific approach to learning physiology that has carried them through their earliest years of science education, and instead adopt a more general and conceptual approach that ultimately advances their level of learning. To help promote this effort in our Bachelors-level Physiology degree program, we have developed a Core Concepts in Physiology Seminar – a required, one-credit course delivered as part of our program's second year curriculum. The seminar immerses students in the core concepts approach, unfettered by the content-heavy demands of the typical anatomy & physiology survey courses. Delivered while the students are co-enrolled in the second half of a year-long anatomy & physiology lecture and laboratory sequence, the seminar can draw on the foundational content of those course while placing its emphasis on student creation of general models2, and allow students to share and discuss the application of critical core concepts such as flow down gradients, energy, cell-cell communication, and homeostasis. While the core concepts are also being introduced in the anatomy & physiology courses, the seminar provides a low-risk environment for challenging students' approach to learning, with the desired outcome of increasing student adoption of the more integrative and general core concepts approach. 1 Modell, H., Adv. Physiol. Educ. 23: 101-107, 2000. 2 Michaels, J et al. The core concepts of physiology: A new paradigm for teaching physiology. DOI 10.1007/978-1-4939-6909-8, Springer, 2017.

Supported by The University of Scranton

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.
Cardiac Na/K-ATPase alpha1 isoform-specific role in hypertrophic response: role of metabolic and oxidative signaling
Authors: Pessoa Marco , Marck Pauline , Perdoncin Maddie , Collins Dominic , Cai Liquan , Tian Jiang , Artigas Pablo , Blanco Gustavo , Xie Zijian , Pierre Sandrine
Published: May 2023

Cardiac Na/K-ATPase (NKA) inhibition by cardiotonic steroids (CTS) modulates intracellular Na+ and Ca2+, leading to increased force of contraction. In contrast, hypertrophy of cardiomyocytes (CM) is triggered by CTS through stimulation of reactive oxygen species (ROS) and fetal gene re-expression independently of changes in intracellular Na+ or Ca2+. Based on recent evidence that NKAα1 serves an isoform-specific function in the regulation of oxidative metabolism and ROS generation, we used a genetic approach in the mouse and in human cardiac cells (AC16) to test the hypothesis that NKAα1 is required for cardiac hypertrophy. Cardio α1-/- mice, a conditional KO of NKAα1 in the heart, were viable without overt abnormality of cardiac structure or function. NKAα1 was undetectable in heart lysates or isolated CM of adult cardio α1-/- mice. Despite a compensatory upregulation of NKAα2, Na/K-ATPase activity in crude heart homogenates and NKA currents in CM were reduced by about 60%. Decreased ROS (assessed by total protein carbonylation) and reduced fatty acid oxidation (FAO) and oxidative phosphorylation pathways (revealed by RNA-seq analysis) were noted at baseline. RT-qPCR revealed downregulated genes involved with FAO and the electron transport chain (such as, Acadl and Ndufa9, about 20% decrease, n=6) in cardio α1-/- hearts. The activity of the electron transport chain complex I was decreased in cardio α1-/- hearts (0.3354 vs 0.2732 mOD/min/mg of protein, p<0.05). When 3-month-old male mice were challenged with angiotensin II (1.5 mg.kg-1.day-1 for 1 week, n=6-15), cardio α1-/- mice did not develop cardiac hypertrophy, as assessed by heart weight to tibia length ratio, but displayed exacerbated cardiac fibrosis, revealed by Trichrome staining, consistent with the postulated role of CM NKAα1 isoform-specific function in cardiac hypertrophy in vivo. In vitro, CRISPR-Cas9-mediated KO of NKAα1 in AC16 cells led to a drastic downregulation of NKAα1 compared to WT AC16 cells. In contrast to WT AC16 cells, NKAα1 KO cells did not respond to the α-adrenergic agonist phenylephrine (50 μM for 24h) with the expected increase in cell area (2243 vs 3520 μm2 for WT, p<0.05; 2454 vs 2563 μm2 for KO, p>0.05). These data suggest that NKAα1 isoform-specific function is required for cardiac hypertrophy. Mechanistically, our data support an isoform-specific regulatory function of NKAα1 in normal FAO, electron transport chain activity, and ROS generation, which are critical for CM hypertrophy.

Supported by NIH Grant R15 HL145666 and American Heart Association Grant 22POST917776 (Marco T. Pessoa)

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.
Acetaminophen causes mitochondrial dysfunction in heart cardiomyocytes
Authors: Rivera Gabriela , Sule Rasheed , Gomes Aldrin
Published: May 2023

Acetaminophen (APAP) is a common over-the-counter medication used to treat pain and fever. It can be taken orally, topically, or intravenously and is considered a safe and effective drug when taken at therapeutic doses. However, recent research suggests that taking APAP regularly can result in increased blood pressure and cardiovascular risk. Previous publications found that Non-Steroidal-Anti-Inflammatory-Drugs (NSAIDs) increased Reactive Oxygen Species (ROS) in cardiomyocytes, resulting in cardiac dysfunction. Although APAP is not a NSAID, APAP likely has similar effects. We hypothesized that regular APAP usage resulted in increased ROS levels, leading to potential dysfunction in hearts and other organs. We used the embryonic rat heart cell line H9C2 to test our hypothesis. We conducted a ROS Assay using H9C2 cells treated with dichlorodihydrofluorescein diacetate (DFCDA). The cells were then treated with vehicle, various concentrations of APAP (25μM, 50μM, 100μM, and 200μM), or 100μM hydrogen peroxide for 1.5 hours before measuring the ROS levels of the cells. We also measured the cell viability of H9C2 cells. Cells were treated with 10μM Alamar Blue, then treated with vehicle, various concentrations of APAP (25μM, 50μM, 100μM, and 200μM), or 100μM or 200μM hydrogen peroxide for 48 hours before detecting the percentage of viable cells. The mitochondrial membrane potential (MMP) of cells treated with APAP was also measured. Cells were treated with vehicle, various concentrations of APAP (25μM, 50μM, 100μM, and 200μM), or 250μM p-triflouromethoxyphenylhydrazone (FCCP) for 24 hours before being incubated with JC-10 for one hour. The cells were measured using a fluorescent reader at excitation/emission 490/525 nm and 540/590 nm. For the ROS assay, the cells treated with 100μM APAP, 200μM APAP, and 100μM Hydrogen Peroxide significantly increased total ROS compared to the control. The cell viability assay resulted in a significant decrease in percent viability in cells treated with 200μM APAP, 100μM hydrogen peroxide, and 200μM hydrogen peroxide compared to the control. The MMP Assay resulted in a significant decrease in MMP at all concentrations of APAP and 250μM FCCP compared to the control. These results suggest that treatment of H9C2 cardiac cells with physiological concentrations of APAP causes an increase in intracellular ROS levels, decreased cell viability, and decreased MMP. Overall, APAP causes mitochondrial dysfunction, which is likely to cause cardiomyocyte dysfunction.

This research is funded by the NIEHS/Superfund Research Program (P42 ES004699).

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.
Increased renal dysfunction and neutrophil infiltration in a mouse model of psoriasis
Authors: Chen Ziche , Meyer Jason , Ward Nicole , Alexander Matthew
Published: May 2023

Psoriasis is a chronic inflammatory skin disease affecting 2-5% of the global population. As an autoimmune disease, psoriasis is characterized by T cell-mediated hyperproliferation of epidermal keratinocytes. Interestingly, most of the morbidity and mortality from psoriasis is related to increased risk of cardiovascular and renal disease. For example, moderate to severe psoriasis is associated with an approximately 1.5-fold increased risk of chronic kidney disease. Neutrophils are increased in the skin and circulation of patients with psoriasis, and markers of neutrophil activation are associated with extra-cutaneous manifestations of psoriasis including vascular inflammation. However, the molecular mechanisms linking psoriasis and kidney disease remain unclear. We hypothesized that increased neutrophil infiltration of the kidney through enhanced granulopoiesis promotes renal dysfunction in psoriasis. Using a KC-Tie2 mouse model of psoriasis with keratinocyte-specific overexpression of the angiopoietin receptor Tie2, we found that KC-Tie2 mice compared to littermate controls exhibit significantly increased urine albumin, suggestive of renal dysfunction. KC-Tie2 mice also exhibit significantly increased kidney/body weight and heart/body weight ratios compared to littermate controls. To determine a mechanism for the increased renal dysfunction in these mice, we assessed skin and renal immune cell content using flow cytometry. KC-Tie2 mice had increased neutrophils in the skin, as well as an approximately 10-fold increase in neutrophils in the kidneys. This increase in renal neutrophils in KC-Tie2 mice was relatively selective as there were no differences in the number of renal dendritic cells, lymphocytes, or monocytes and a modest but significant increase in macrophages. We also observed a selective increase in neutrophils in the spleen of KC-Tie2 mice. Given these findings and prior reports of increased circulating neutrophils in KC-Tie2 mice, we assessed mediators of granulopoiesis in the serum and found a significant increase in granulocyte colony stimulating factor (GCSF) in KC-Tie2 mice. Taken together, these results provide evidence for increased renal dysfunction in a mouse model of psoriasis coincident with marked increases in renal neutrophils that may represent a novel mechanism linking skin inflammation to renal dysfunction through enhanced granulopoiesis.

MRA is funded by NIH K08HL153786-01. JM is funded by 2T32GM007569. NW is funded by NIH R01 AR075777, NIH R01 AR073196, NIH P50 CORT AR070590, and National Psoriasis Foundation.

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.
Impact of intranasal insulin on cerebral blood flow and cerebrovascular reactivity in healthy young adults
Authors: Shariffi Brian , McMillan Neil , Jacob Dain , Harper Jennifer , Manrique-Acevedo Camila , Padilla Jaume , Limberg Jacqueline
Published: May 2023

Objective: Adults with obesity and insulin resistance exhibit impaired cerebrovascular reactivity and endothelial dysfunction, which increases the risk of dementia and Alzheimer’s disease. Impairments in cerebrovascular health have been attributed to vascular insulin resistance and emerging data support the use of intranasal insulin as a potential therapeutic intervention. Although mechanisms are unclear, the benefits of intranasal insulin may in part be mediated by changes in cerebral blood flow and/or cerebrovascular reactivity. Using intranasal administration of insulin, we examined the acute effect of central insulin on resting cerebral blood flow as well as reactivity to inhaled carbon dioxide. We hypothesized intranasal insulin would increase indices of cerebral blood flow and cerebrovascular reactivity in healthy young adults. Methods: Nineteen healthy young adults were randomized into time control [n=12 (5F/7M), 27±1 yrs, 25±3 kg/m2] or 160 IU of intranasal insulin administered over 5 min [n=7 (0F/7M), 27±3 yrs, 25±3 kg/m2]. Carotid artery blood flow (CBF, Doppler ultrasound) and middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) were measured prior to and 60 min following insulin administration and/or time control. In a subset of participants (time control, n=10; insulin, n=5), cerebrovascular reactivity was assessed as the relative (%) increase in MCAv and CBF from baseline during 3 min of carbon dioxide air breathing (+7.5±0.5 mmHg). Results: Blood glucose and plasma insulin remained unchanged throughout the protocol (both, p>0.05). CBF (712±39 to 727±40 mL/min, p=0.45) and MCAv (50±3 to 52±3 cm/s, p=0.50) remained at baseline levels following the 60-min time control condition. Similarly, resting CBF (901±60 to 908±58 mL/min, p=0.78) and MCAv (54±5 to 52±5 cm/s, p=0.41) did not differ from baseline following intranasal insulin administration. Carbon dioxide breathing led to an elevation in CBF and MCAv, and their respective increases were unaffected by time control (33±5 to 37±7%, p=0.58; 49±6 to 58±9%, p=0.32) or intranasal insulin (25±3 to 24±5%, p=0.93; 39±6 to 46±6%, p=0.49). Conclusions: Contrary to our hypothesis, acute intranasal insulin administration had no effect on indices of cerebral blood flow and/or cerebrovascular reactivity in healthy young adults. Future studies should examine the cerebrovascular effects of intranasal administration in disease states ( e.g., obesity, insulin resistance, Alzheimer’s disease).

CAFNR Joy of Discovery (JKL, JP)

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.