bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beneficial cardiovascular-renal effects of exercise on aging male and female obese TallyHo/Jng mice
Authors: Wadhwa Vishwas , Gadicherla Arushi , de Souza Aline , Korolowicz Kyle , Ecelbarger Carolyn 
Published: May 2023

The benefits of aerobic exercise on cardiorenal health in aging, insulin-resistant individuals are not fully understood. We hypothesized that chronic treadmill exercise (aerobic training) of overweight aging (10-month old) insulin-resistant TallyHo/Jng (TH) mice (prone to type 2 diabetes) would improve the comprehensive cardiovascular phenotype and metabolism. Male (M) and female (F) TH mice (n = 10/group) underwent treadmill running exercise (Ex, 10-19 meters/min) for 15-30 minutes, 4X/week or remained sedentary (Sd) for 9 weeks. Final body weights were 20 and 30% lower in M and F Ex, relative to same sex Sd groups, respectively. Ultrasound conducted a week prior to euthanizing showed renal blood flow (external velocity, pulse wave doppler) was significantly increased by Ex on average 26 and 24% in M and F, respectively (2-way ANOVA for Ex, p = 0.0089). With regard to cardiac features, while cardiac output was not significantly different between groups, stroke volume was increased in both sexes by Ex (9% in M, 5% in F). Whereas, cardiac ejection fraction and fractional shortening were significantly increased by Ex in female, but not male mice (p < 0.03 between FEx and FSd groups by Šidák's multiple comparisons testing). Left ventricular mass was not altered by Ex, but about 20% higher in M than F mice. Dual X-Ray Absorptiometry (DEXA) scanning revealed increased bone mineral content and density, in both sexes due to Ex, as well as, reduced body fat, but only in the F mice (p < 0.0001). Body fat was (%): 26.1 ± 0.4 (MSd); 26.1 ± 0.6 (MEx); 31.7 ± 1.8 (FSd); 20.8 ± 1.1 (FEx). Total lean mass was significantly higher in M, but not affected by Ex. Ex reduced final blood glucose (4-hour fasted, p = 0.0007 for Ex, mg/dl): 142 ± 5 (MSd); 128 ± 5 (MEx); 137 ± 4 (FSd); 117 ± 4 (FEx). Most fat pads (weighed at euthanasia) were reduced in mass in the F by Ex, but not necessarily in the M. Brown fat was increased by exercise in M, but reduced in F (g/40 g·bw): 0.34 ± 0.02 (MSd); 0.44 ± 0.03 (MEx); 0.37 ± 0.03 (FSd); 0.25 ± 0.04 (FEx), p = 0.0007 for interaction of exercise with sex (2-way ANOVA). Kidney, liver, and heart final wet weights were not affected by Ex, but lower in F (p < 0.0001 for sex for all 3). In conclusion, treadmill exercise to obese, aging TH M and F mice resulted in a several improved cardio-renal indices in addition to reducing weight, visceral fat mass, and increasing bone density. These studies support the prescription of vigorous cardiovascular exercise in aging, obese, insulin-resistant individuals. Funding to CE provided by the Marriott Foundation, the NIH CTSA Award pre-pilot, and internal Georgetown University 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.
Effects of the thromboxane receptor antagonist S18886 in the porcine coronary circulation
Authors: Tucker Selina , Warne Cooper , Essajee Salman , Goulopoulou Styliani , Dick Gregory , Tune Johnathan 
Published: May 2023

Thromboxane A2 (TxA2) is a potent coronary vasoconstrictor that has been implicated in promoting decreases in myocardial perfusion in a variety of (patho)-physiologic conditions. S18886 is a promising orally-active TxA2 receptor antagonist currently approved for investigational clinical use. However, the coronary vascular effects of S18886 are unknown and its specificity and affinity for the thromboxane receptor in the coronary circulation remain unclear. We tested the hypothesis that administration of S18886 dose-dependently attenuates coronary vasoconstriction to the TxA2 mimetic U46619 without influencing coronary responses to prostaglandin F2α, acetylcholine, or smooth muscle depolarization (K+). Experiments to test this hypothesis were performed in male (n = 5) and female (n = 6) domestic swine. Hearts were excised and the left circumflex coronary artery isolated, cleaned of periadventitial fat, and cut into 3 mm rings. Isometric tension of coronary artery rings was measured in response to log order increments of U46619 (1 nM to 1 μM) with and without S18886 (0.1-100 nM). Similar isometric studies were conducted with prostaglandin F2α (10 nM-10 μM), acetylcholine (0.1-10 μM), and KCl (5-90 mM). U46619 induced concentration dependent increases in tension development of isolated coronary artery rings (average EC50 of 42 ± 19 nM). Incubation of coronary arteries with S18886 (1 nM) significantly attenuated coronary vasoconstriction to U46619 resulting in a rightward shift of the EC50 to 187 ± 38 nM (P < 0.02). Vehicle had no effect on U46619-induced contractions. Higher concentrations of S18886 (10nM and 100nM) dose-dependently reduced U46619-induced contractions by 77% ± 3 and 93% ± 6 respectively. S18886 (1 nM) antagonized coronary vasoconstriction of prostaglandin F2α (10 μM) by 68% ± 5 (P < 0.0001) but had no effect on either acetylcholine or KCl-induced contraction. Data from this investigation indicate that S18886 is an effective antagonist of U46619-induced vasoconstriction in the porcine coronary circulation. While S18886 does not influence coronary smooth muscle response to either acetylcholine or activation of L-type Ca2+ channels, attenuation of prostaglandin F2α suggests the antagonists specificity may extend beyond TxA2 receptor signaling. NIH R01HL158723 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.
Exertional heart stroke causes long-term obesity and cardiac hypertrophy in mice
Authors: Alzahrani Jamal , Gambino Bryce , Delgado Cristina , Rua Michael , Young Iris , Cusack Kevin , Clanton Thomas 
Published: May 2023

Exertional heat stroke (EHS) is a life-threatening illness that can lead to short- and long-term adverse health outcomes. Several human epidemiology studies have shown that heat stroke exposure is highly associated with the development of cardiovascular disease later in life. However, whether EHS causes heart disease or individuals with predispositions to heart disease are more susceptible to EHS is unknown. Previously, our laboratory demonstrated metabolic abnormalities in the myocardium of mice, two weeks after EHS, characterized by lipid accumulation. In this study, we hypothesized that EHS exposure in mice leads to long-term susceptibilities to cardiovascular disease that is accelerated by co-exposure to a Western diet. METHODS: Sixty-four male (n=32) and female (n=32) C57BL/6 mice were exposed to either EHS (forced wheel running in 34.5°C for males and 37.5°C for females) or sham exercise controls (EXC, forced wheel running in ~22.5°C). Fourteen days later, mice were placed on either a Western diet (WD) or a standard diet (SD) and then followed for 9 additional weeks. At week 12, post interventions (EHS or EXC), animals were euthanized and samples collected for analysis. RESULTS: Male mice exposed to EHS with either WD ( P = 0.0001) or SD ( P = 0.0001) gained more body mass over the 9-week diet period compared to diet matched EXC controls. Also, regardless of diet, male mice exposed to EHS consumed more food compared to matched EXC (WD: P < 0.005 and SD: P < 0.04). However, only female mice exposed to EHS with WD gained more body mass compared to female EXC mice with WD ( P < 0.04). At the end of the study, and regardless of diet, male mice exposed to EHS showed enlarged hearts in terms of absolute mass (WD: P=0.0241, SD: P=0.0069) and relative mass/tibia length (WD: P=0.013, SD P=0.03). On the other hand, EHS female mice exposed to WD showed enlarged heart mass compared to EHS on SD ( P=0.0005). CONCLUSIONS: These results demonstrate that EHS exposure in mice leads to a long-term metabolic disorder characterized by greatly accelerated weight gain, greater appetite and cardiac hypertrophy. Effects were more evident and consistent in males. Such a response is typical of early stages of metabolic syndrome and would likely contribute to eventual cardiac disease. Therefore, the data is consistent with EHS exposure being a risk factor for long term heart disease. U.S. Army Grant BA180078 and from King Saud University, Saudi Arabia 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.
Rare Single-Nucleotide Variants that Impact Human ENaC Function
Authors: Chen Mindy , Chen Jingxin , Wang Xueqi , Sheng Shaohu , Kleyman Thomas 
Published: May 2023

While single-nucleotide variants (SNV) in ENaC coding region occur throughout functional domains, only a few SNVs exhibit pathophysiological phenotypes with mendelian inheritance. Since a SNV that alters ENaC’s ability to sense extracellular Na⁺ has been linked to hypertension, we hypothesize that other ENaC SNVs that alter channel activity will also affect blood pressure. To identify novel low-frequency ENaC SNVs that change ENaC activity, we heterologously expressed human ENaC gamma subunit variants together with wildtype alpha and beta subunits in Xenopus oocytes. We performed two-electrode-voltage clamp (TEVC) to record amiloride-sensitive currents of these channels. We characterized rare human SNVs found in multiple genomic databases covering various γENaC domains. Among the selected SNVs, we identified three gain-of-function variants (γV110I, γG149A, γV619L) with significantly greater amiloride sensitive currents (P<0.001, n=25~55) than wildtype channels. In addition, two loss-of-function variants (γG58R, γH280R) displayed significantly decreased currents (P<0.001, n=20~25) than wildtype channels. Future studies investigate the functional effects of these SNVs by assessing the gating behavior and surface expression of these channels. These data suggests that: Although low in prevalence but high in coverage throughout the ENaC coding region, rare SNVs directly modify the channel function. Our results add the growing list of human ENaC variants that alter channel activity and could impact blood pressure in humans. National Institutes of Health Grants R01 HL147818 and P30 DK079307 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.
Pressure induced changes in endothelial cell morphology and Ca2+ signaling in ex vivo pressurized resistance arteries revealed using 4D diSPIM myography and AI deep-learning
Authors: Al-Aqtash Rua'a , Collier Daniel 
Published: May 2023

The vascular endothelium is critical in promoting vasodilation of resistance-size arteries through Ca2+ dependent pathways. Vascular endothelial cells (ECs) are exposed to mechanical stimulation through changing intravascular pressure and flow, yet it is unclear how these forces impact EC morphology and Ca2+ signaling in pressurized arteries. Visualizing how the endothelium of an intact resistance-size vessel responds to changing physical forces requires isometric, sub-micron, resolution. Conventional confocal fluorescent microscope systems are limited by poor axial resolution. 4D dual inverted selective plane of illumination microscopy (diSPIM; 3i) uniquely provides isometric resolution at ~330 nm with high temporal resolution and minimal photobleaching or phototoxicity. We designed custom pressure myography chambers to allow simultaneous 4D diSPIM fluorescent imaging and vessel diameter tracking measurements via transmitted IR light (diSPIM Myography). We captured fluorescent images of ex vivo pressurized resistance-size mouse mesenteric arteries at 80, 60, 40, and 20 mm Hg before and after the generation of myogenic tone and in the absence of extracellular Ca2+. Representative images were annotated for ECs, nuclei, myoendothelial projections (MEPS), and Ca2+ signals. Annotations were used as ground truth for CNN AI model generation and validation using Apeer (Zeiss). Arivis Vision4D (Zeiss) was used to run the AI model and quantify data. As static intravascular pressure is increased in arteries without tone (with or without Ca2+), ECs increase in width as the vessel dilates. Myogenic tone minimizes pressure dilation and changes in EC width, however, ECs compress by up to 1 micron as pressure increases from 20 to 80 mm Hg. Additionally, increasing intravascular pressure in arteries with tone decreases local EC Ca2+ signaling. The data demonstrate a relationship between intravascular pressure and EC shape and Ca2+ signaling in intact resistance arteries under conditions of physiologic temperature, pressure, pH, and tone. diSPIM myography provides a method of studying the effects of physiologically relevant mechanical stimuli and the roles of various mechanosensitive mechanisms on vascular function. AI image annotation reduces analysis bias and increases the breadth of quantifiable microscopy data. DMC is supported by NIH R00HL133451 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.
Investigation of the role of ATPase Inhibitory Factor 1 in pulmonary arterial hypertension
Authors: Brown Zachary , Batori Robert , Sellers Hunter , Haigh Stephen , Bordan Zsuzsanna , West Madison , Barman Scott , Fulton David 
Published: May 2023

Pulmonary arterial hypertension is a rare and debilitating condition with a five-year survival rate of only 34% without treatment. The origins of pulmonary arterial hypertension are complex and incompletely understood and elevated pulmonary artery pressures result from excessive vascular remodeling due to functional changes in endothelial, vascular smooth muscle cells (VSMCs), and adventitial cells. Recent papers have explored the importance of metabolic switching of VSMCs in pulmonary hypertension in the transition towards a proliferative, apoptotic resistant phenotype which involves a shift from fatty acid oxidation to increased glycolysis. We hypothesized that ATPase Inhibitory Factor 1 (ATPIF1) in VSMCs could function as a metabolic switch that promotes a shift from fatty acid oxidation to glycolysis to increase the severity of pulmonary arterial hypertension. This hypothesis will be investigated using Western blot, Seahorse extracellular flux assays, qRT-PCR, and imaging of GFP-labelled ATPIF1. In preliminary data, we have cloned ATPIF1 and transfected cells to show overexpression of ATPIF1 decreases the maximal respiratory rate while increasing extracellular acidification, a measure of glycolysis. Future goals are to investigate the links between hypoxia, hypoxia-inducible factors and ATPIF1, the role of increased glycolysis in pulmonary smooth muscle cells, and ultimately whether ATPIF1 impacts of the development of pulmonary arterial hypertension in mice. 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 relationship between CFTR expression and cAMP-stimulated bicarbonate secretion diverges for the duodenum and ileum of pig
Authors: Mujica Rebecca , Thornell Ian 
Published: May 2023

The luminal pH of the small intestine influences the digestion and absorption of nutrients. HCO3– secretion from Brunner’s glands and the ampulla of Vater initially alkalinize the acidic chyme upon entering the small intestine, and less-frequent Brunner’s glands and the surface epithelia of the small intestine further alkalinize chyme as it moves away from the ampulla of Vater. People with cystic fibrosis alkalinize chyme more slowly than their peers, suggesting that the anion channel CFTR (cystic fibrosis transmembrane conductance regulator) participates in the alkalinization. To further understand the relationship between CFTR expression and HCO3– secretion across duodenal and ileal epithelia, we studied newborn pigs with disrupted CFTR alleles ( CFTR–/–) and their littermates ( CFTR+/– and CFTR+/+). We hypothesized that CFTR–/– pigs would lack HCO3– secretion and that CFTR+/– pigs would have decreased HCO3– secretion because of reduced CFTR expression. To measure the electrogenic HCO3– secretion rate, we recorded short-circuit current ( Isc) across resected intestinal tissue bathed in solutions containing gluconate and HCO3–. Forskolin/IBMX-stimulated Isc across the duodenum of CFTR+/– pigs was half the rate observed for CFTR+/+ pigs, and forskolin/IBMX-stimulated Isc was absent across CFTR–/– duodenum. However, Isc across the ileum was similar between CFTR+/+ and CFTR+/– pigs and absent across CFTR–/– ileum. CFTR–/– pigs expressed CFTR mRNA transcripts at nominal levels for both intestinal segments, whereas CFTR+/– pigs expressed half the CFTR mRNA transcripts of CFTR+/+ littermates for each intestinal segment. These data are consistent with CFTR involvement in neutralizing luminal contents in the duodenum and ileum. Furthermore, these data suggest that the relationship between CFTR expression and the electrogenic HCO3– secretion rate diverges for these two intestinal segments. Electrogenic HCO3– secretion in the duodenum directly relates to CFTR expression, whereas electrogenic HCO3– secretion across the ileum appears to saturate at a CFTR expression level between CFTR–/– and CFTR+/– pigs. Cystic Fibrosis Foundation Research Development 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.
Timed Release Ion Matrix Enhances Muscle Force in Dystrophic Mice
Authors: Kendra Jacob , Brow Richard , Segal Steven , Morton Aaron 
Published: May 2023

Background: Duchenne Muscular Dystrophy (DMD) is an x-linked, recessive chromosomal mutation of the gene dystrophin, affecting 1 in 3,500 males. DMD is associated with limb muscle dysfunction from repetitive damage to myofibers beginning at 2 years of age. In healthy muscle, dystrophin is responsible for maintaining the sarcolemma through the dystrophin-glycoprotein complex, while muscle with dystrophin deficiencies seen in DMD patients experience severe sarcolemmal disruption following muscle contraction. Despite major advances in genetic engineering, the functional outcomes of FDA-approved therapeutic strategies have failed to enhance the function of dystrophin-deficient myofibers. We have taken an alternative approach to apply a novel biomaterial, Time Release Ion Matrix (TRIM), that has the potential to release ions favorable to regeneration, restoring muscle structure and function in DMD mice. Hypothesis: We hypothesized that muscle force and myofiber cross-sectional area (CSA) of the tibialis anterior muscle (TA) in an established mouse model of muscle dystrophy [D2.B10 mdx (DBA. mdx)] would be enhanced 14 days post-injection of TRIM. Methods: The left TA of adult male DBA. mdx mice (n=3-9, age 6-7 months) was injected with 250 μg of TRIM suspended in saline or saline alone (vehicle control). At 14 days post injection, the TA muscle was isolated for in situ muscle force measurements using direct electrical stimulation. The TA was then removed and frozen in optimal cutting temperature compound (OCT) for histological analysis. Muscle cross-sections (thickness, 10 μm) were labeled with laminin to identify myofiber borders and myosin heavy chain as a marker of myofibers able to generate force. Images were analyzed using Nikon NIS-Elements software. To simulate body fluid, 300 mg of TRIM was suspended in physiological salt solution (PSS) for 120 hours. Results: The dissolution of TRIM in PSS over 120 hours was 40% (179 mg remaining). Peak isometric force of TAs injected with TRIM (60.0 ± 2.3 g) was 11% greater compared to saline alone (52.4 ± 2.4 g) (means ± SE, n=6-9 per group; P=0.048). There were fewer small diameter myofibers (< 400 μm2) in TAs injected with TRIM (10 ± 7%) compared to saline controls (24 ± 5 %) (n=3/group; P=0.03). Conclusion: 14 days following injection of TRIM into the TA of dystrophic mice, muscle force and myofiber CSA were enhanced by 11 and 14% respectively. We suggest that TRIM may be an effective treatment to restore muscle function in DMD and serve as a powerful tool for discovering therapeutic targets against DMD. University of Missouri Coulter Biomedical Accelerator (SSS, ABM), Texas A&M Department of Kinesiology and Sport Management (JAK, ABM) 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 activators of NF-KB to model inflammation
Authors: Shivers Mitch , Sellers Hunter , Brown Zachary , Haigh Stephen , Bordan Zsuzsanna , West Madison , Batori Robert , Stepp David , Fulton David 
Published: May 2023

Chronic inflammation underlies many chronic diseases such as obesity and diabetes and can lead to vascular and organ dysfunction, disability and death. Inflammation has been widely studied due to its broad involvement in numerous disease states, but current models of inflammation suffer from limitations. Models such as LPS treatment are non-specific and require multiple doses over extended periods of time which can lead to septic shock. The goal of our study was to develop an alternative model offering cell and organ specificity using an AAV-based approach. We hypothesize that delivering Ikk2, a potent activator of NF-KB will lead to chronic inflammation in the targeted cells and tissues. This approach has the benefit of cell and tissue specificity using specialized promoters and modified AAV capsids. Additionally, it will allow for consistent and regulatable expression over time. In preliminary studies I compared two know activators of NFKB, IKBKE and IKK2 to investigate differences in expression of inflammatory markers. Western blot analysis revealed ICAM-1 and IRF-1 protein levels were increased with IKK2 expression. In comparison, the inhibitior of apoptosis, CIAP-2, was more highly increased under IKBKE expression. We conclude that IKK2 would be more suitable to induce inflammation in target cells. Future studies will employ qPCR, Western blot, cytokine analysis and vascular function studies to characterize the effects in vivo. 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.