bluuebunny/crossref_metadata_2025_split huggingface dataset:
Consequences of Transient YAP Signaling in the Liver
Authors: Alcedo Karel , Samey Oksanna , Biju Isaac , Sun Liang , Camargo Fernando 
Published: May 2024

The transcriptional co-activator YAP plays a complex role in liver homeostasis and disease development. In response to liver injuries and hepatotoxins, YAP is transiently activated to promote liver regeneration by coordinating cell proliferation and metabolism. By contrast, chronic activation of YAP in experimental models has been associated with liver diseases and cancer. These primary responses to YAP are well established; however, it is presently unknown how acute YAP signaling contributes to the eventual development of liver diseases. Here, we developed an in vivo model of dynamic YAP signaling using a doxycycline-inducible system to control the transient expression of a constitutively active YAP mutant in hepatocytes. We found that while YAP-dependent effects on liver growth and cell proliferation are reversible, there are metabolic changes in the liver that remain stable even after YAP inactivation. By coupling RNAseq and ATACseq analyses, we unraveled persistent changes in gene expression and chromatin accessibility, particularly those involved in lipid metabolism. Furthermore, we demonstrated that transient YAP signaling sensitizes the liver to develop more severe liver injuries than normally induced in an unprimed liver. These data suggest that transient YAP signaling imparts a form of lipid metabolic memory that promotes susceptibility to liver diseases. Overall, our current work reveals long-term consequences of acute YAP signaling that may influence the development of liver diseases. 5R01HL128850-07 (FC) and 5T32DK007477-40 (KA). This is the full abstract presented at the American Physiology Summit 2024 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 modulating pulmonary artery pressure on resting right ventricular function in endurance-trained and untrained individuals
Authors: Brotto Andrew , D'Souza Andrew , Foulkes Stephen , Rampuri Zahrah , Kesslar Keanne , Fuhr Desi , Haykowsky Mark 
Published: May 2024

Prolonged endurance training is associated with critical adaptations to right ventricular (RV) structure and function that facilitate the achievement of higher exercise capacity, peak cardiac output, and RV stroke volume in the face of large increases in pulmonary artery pressures (afterload) and RV wall stress. Compared to the left ventricle, the RV is more sensitive to increases in afterload during exercise. However, the independent effect of increased afterload on RV function in endurance trained (Trained) vs untrained individuals remain unknown. Trained were considered those with a maximal oxygen consumption ( V̇O2max) >60ml/kg/min (male) or >55ml/kg/min (female) while untrained were defined as V̇O2max <45ml/kg/min. Using echocardiography, this retrospective study sought to evaluate RV systolic function (RV global longitudinal strain [GLS]) and ventriculo-arterial coupling (ratio of RV GLS to pulmonary artery systolic pressure [PASP]) in Trained and untrained individuals while manipulating PASP. Ten participants (5 Trained and 5 Untrained) underwent resting echocardiography while breathing moderate (pressure of inspired oxygen; PiO2=89 mmHg) and severe hypoxia (PiO2=79 mmHg; order randomized) to increase PASP. Separately, eight participants (4 Trained and 4 untrained) inhaled nitric oxide (iNO; 40ppm) during echocardiography to lower PASP. Moderate and severe hypoxia increased PASP by 2.3 ± 1.3mmHg and 3.5 ± 1.8mmHg, respectively, while iNO decreased PASP by 2.6 ± 2.4mmHg, with no between group differences observed. Cardiac output was not different between any condition. A fitness-by-hypoxia interaction was observed in RV GLS in moderate hypoxia suggesting Trained had lower RV function during moderate hypoxia as compared to untrained (Untrained: -23.1 ± 4.4% vs. Trained: -20.2 ± 2.7%; p<0.01). No differences in RV GLS were observed with iNO (p=0.98). The ratio of RV GLS to PASP was significantly different between groups at moderate hypoxia (Untrained: -1.06 ± 0.09%/mmHg vs. Trained: -0.85 ± 0.12%/mmHg; p=0.04) but not severe hypoxia (p=0.78). These findings suggest reducing PASP did not alter RV function or ventriculo-arterial coupling, however, Trained individuals experienced differential RV function responses when PASP is experimentally increased with hypoxia. Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2024 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.
PERK specific inhibitor AMG-44 protects against Trimethylamine N-oxide (TMAO)-induced Endoplasmic Reticular Stress and Endothelial Dysfunction
Authors: Koka Saisudha , Pasham Sindhura , Boini Krishna M. 
Published: May 2024

The gut microbiota is known to release metabolites detrimental to the endothelial cell lining of the vascular wall leading to endothelial dysfunction. We have earlier reported that Trimethylamine N-oxide (TMAO), an intestinal microbe derived metabolite, caused endothelial dysfunction. In the present study we hypothesized that protein kinase R-like endoplasmic reticulum kinase (PERK)/eIF2α/ATF4 signaling is involved in TMAO-induced endoplasmic reticular (ER) stress and that treatment with PERK inhibitor AMG-44 protects against TMAO-induced ER stress. The endothelial cells were treated with a range of increasing doses of TMAO (0-300 μM) to induce ER stress. PERK inhibitor AMG-44 (20 – 200nM) was used to treat the TMAO treated and control cells. TAMO showed a dose-dependent upregulation of ER stress marker proteins involved in the PERK/eIF2α/ATF4 ER-stress signaling pathway. Western blot analysis showed significant increase in p-PERK/PERK, p-eIF2α/eIF2α, and IRE1α, AFT-4 protein expression which was further confirmed by immunofluorescent analysis in endothelial cells. Treatment with AMG-44 significantly attenuated the PERK/eIF2α/ATF4 axis also protected against increased endothelial cell permeability induced by TMAO (n=6/group; p<0.05). Our results demonstrate that TMAO-induced endothelial dysfunction via the ER stress-mediated PERK- eIF2 α -ATF4 signaling pathway and that treatment with PERK specific inhibitor AMG-44 could be a novel therapeutic strategy in protection against TMAO-induced ER stress and endothelial dysfunction. NIH R01HL148711 to Dr. Sai Sudha Koka. This is the full abstract presented at the American Physiology Summit 2024 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.
Freshly isolated bone marrow monocytes from mice lacking βENaC or ASIC2 have sex-linked reduced chemotactic migration responses
Authors: Wasson Robert , McLin Je'la , Hildebrandt Emily , Drummond Heather 
Published: May 2024

The monocyte-macrophage system plays an important role in phagocytosis of pathogens and cellular debris following infection or tissue injury. Circulating monocytes differentiate into macrophages which can be polarized into pro- or anti-inflammatory phenotypes. A previous study from our laboratory demonstrated the RAW cell monocyte-macrophage line express α and β Epithelial Na+ Channel (ENaC) subunits which contribute to chemotactic migration and polarization. Here we tested the hypothesis that freshly isolated bone marrow monocytes also express ENaC and related Acid Sensing Ion Channel transcripts which may contribute to monocyte migration. Using qRT-PCR, we found α, βENaC and ASIC1-5 are similarly expressed in freshly isolated bone marrow monocytes from wild-type male and female mice. We also examined chemotactic migration in monocytes isolated from global βENaC hypomorph mice and ASIC2 knockout mice. We found migration was differentially inhibited in male and female animals. In ASIC2−/− monocytes, migration was inhibited to 76±2% and 86±2% of control in male and female animals, respectively. In βENaC hypomorph monocytes, migration was inhibited to 74±2% and 56%±3 of control in male and female animals, respectively. These findings suggest that βENaC and ASIC2 contribute similarly to monocyte migration in males, however, βENaC plays a greater role in migration (than ASIC2) in females. The in-vivo role of βENaC and ASIC2 to monocyte responses associated with inflammation has not been addressed. This research was supported by NIH R01HL136884, P20GM104357, P30GM149404, P20GM121334, and P20GM103476. This is the full abstract presented at the American Physiology Summit 2024 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.
Is improved pulmonary vasodilation why endurance trained individuals have elevated diffusing capacity compared to untrained individuals?
Authors: Ehnes Cameron , Collins Sophie , Brotto Andrew , Fuhr Desi , Thompson Stephanie , van Diepen Sean , Stickland Michael 
Published: May 2024

Contrary to our traditional understanding, the pulmonary vasculature may adapt to endurance training. Improved pulmonary vasodilation may be the principal mediator for trained individuals who exhibit greater diffusing capacity (DLCO), capillary blood volume (VC; representing recruitment and distension) and membrane diffusing capacity (DM; representing recruitment) at rest and during exercise as compared to untrained. Potential functional differences may be investigated using pulmonary vasodilators ( e.g., oral sildenafil). The purpose of this study was to examine the effects of sildenafil on DLCO, VC, and DM, in trained and untrained participants. We hypothesized that sildenafil would increase rest and exercise DLCO, VC, and DM, with a lesser relative response in trained due to improved baseline pulmonary vascular function. In this randomized, double-blind, placebo-controlled cross-over design (NCT: 04985929), DLCO was measured at rest (supine and seated) and during cycle ergometry (60 Watts, 30%, 60%, and 90% of V̇O2peak). DLCO was conducted using the modified Roughton-Forster multiple FiO2 breath-hold technique over 6 visits, where participants were given either oral placebo or sildenafil (50 mg, single dose, 30 min wash-in). To date, 18 participants (6 female) (56% target sample size) have been recruited into two groups: trained (T) and untrained (UT) (Mean V̇O2peak = 66.6 ± 7.2 mL.kg−1.min−1 and 37.8 ± 3.2 mL.kg−1.min−1, respectively). Estimated PASP was reduced between placebo and sildenafil across all participants at rest (mean Δ = -2.7 mmHg; p<0.01), indicating effective pulmonary vasodilation. Under placebo, T had higher DLCO at rest (supine), 30%, 60%, and 90% of V̇O2peak (p<0.05), consistent with previous literature. There was no effect of sildenafil on DLCO, VC, or DM (all p>0.200) or drug by workload interactions (all p>0.189) in either group. These preliminary results suggest that pharmacological augmentation of the nitric oxide vasodilatory pathway does not increase DLCO regardless of training status. We speculate that this pathway may not be the primary driver responsible for the elevated DLCO observed in endurance trained participants. Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2024 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.
Hypoxia impairs Kv7 channel function in the coronary microcirculation
Authors: Self Trevor , Heaps Cristine 
Published: May 2024

Ischemic heart disease (IHD) is a multifaceted pathological manifestation that continues to press an extensive burden on individuals and healthcare resources. The strenuous weight of this disease affects more than 80 million people in the United States, with an annual economic cost of more than $300 billion in healthcare expenses and lost productivity. Understanding the progression of this disease and the underlying regulatory mechanisms is essential for dampening the substantial socio-economic burden it poses by supporting the development of novel therapeutic strategies for afflicted patients. Myocardial perfusion is largely controlled by the microcirculation, consisting of small arteries and arterioles. Under physiological conditions, an increase in myocardial metabolic activity stimulates coronary vasodilation and increased vascular perfusion. However, pathological coronary stenosis of the conduit arteries impairs downstream flow and O2 delivery that must be compensated by collateral supply from neighboring nonoccluded regions. The ability of the vasculature to dilate in response to a reduction in flow is paramount for improved perfusion from the collateral circulation. Voltage-gated potassium (Kv) channels present as significant end effectors of vasodilation for many signaling axes, including reactive oxygen species, which are reported to be upregulated under ischemic conditions. Using the clinically relevant swine model for the current study, we isolate a reduction in oxygen tension, ex vivo, as a single characteristic of an otherwise complicated disease and test the hypothesis that hypoxic insult impairs Kv7 channel function. Isometric tension wire myography and perforated patch voltage clamp were used to investigate Kv7 channel contribution to H2O2-mediated vasodilation and Kv channel currents in response to hypoxic insult. Our data reveal that hypoxic conditions impair H2O2-mediated vasodilation and that this impairment is attributable, at least in part, to a loss of Kv7 channel activation. Further, protein kinases are known to associate with and activate Kv7 channels in other tissue types. Inhibition of protein kinase A (PKA) yields a similar inhibitory response to blockade of Kv7 channels. Taken together, these studies reveal Kv7 channels as potential targets of hypoxic insult, and their reduced contribution may be responsible for impaired vasoreactivity in the coronary microcirculation in response to hypoxic insult. Funding: NIH RO1 HL139903. This is the full abstract presented at the American Physiology Summit 2024 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.
Age Comparisons of Cardiac Work During Exercise in Women: Insight from Acute β1 Adrenergic Blockade
Authors: Bowlus Christine , Studinski Matthew , Delgado Spicuzza Jocelyn , Gosalia Jigar , Pawelczyk James , Muller Matthew , Mookerjee Swapan 
Published: May 2024

Postmenopausal women exhibit exaggerated increases in blood pressure during activities of daily living and exercise. The decreased size and increased stiffening of postmenopausal women's hearts elevate myocardial oxygen demand when compared to age-matched men and younger cohorts. Together, this poses a risk to the safety of, and capacity for, exercise in postmenopausal women. We recently studied the effects of esmolol, a fast-acting, cardio-selective β1 antagonist, on oxygen transport variables during dynamic exercise in healthy young (Y) and older (O) women to better understand differences in cardiovascular responses to exercise. Objective: Determine the effects of acute cardiac specific blockade on myocardial oxygen demand (rate pressure product, RPP) and cardiac work (CW) in healthy young premenopausal and older postmenopausal women. Methods: Thirteen healthy young (20-32 yr) and older postmenopausal (58-70 yr) women performed moderate (85% of lactate threshold) and heavy (50% between lactate threshold and the respiratory compensation point) recumbent leg cycling exercise during IV infusion of saline or esmolol in randomized order. Whole body oxygen consumption (VO2, indirect calorimetry), brachial systolic blood pressure (SBP, automated cuff), heart rate (HR, ECG), and cardiac output (CO, bioimpedance) were measured continuously. RPP (HR×SBP), CW (CO×SBP), and cardiac effciency (CE, CW/VO2) were calculated. Mixed model repeated measures ANOVAs were used to determine the effect of treatment and age group. Results: Power outputs were lower in O vs. Y at both moderate (45±9W and 72±15W, p<0.001) and heavy (81±21W vs. 117±32W, p<0.001) intensities. During the saline trial CO was lower (p<0.001), and RPP was higher (p<0.001) in the O vs. Y group during both intensities. There was a main effect of treatment on RPP, CW, and CE. Esmolol reduced RPP (4638±775 SD, p<0.001), CW (547±89, p<0.001) and CE (1682±62, p<0.001) in both O and Y. There was a main effect of age group on CE, pairwise comparisons showed CE was lower in O than Y (441±112, p<0.001). Conclusions: Older postmenopausal women experience higher myocardial oxygen demand and perform more cardiac work for a given whole body liter oxygen consumed during dynamic leg exercise compared to younger premenopausal women. Acute β1 adrenergic blockade narrows the gap between central cardiovascular function in young and old women and provides a powerful tool to investigate age-related cardiovascular differences. NIH R21 AG054940. This is the full abstract presented at the American Physiology Summit 2024 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.
Deletion of Irisin Mitigates HDAC4 Inhibitor-Elicited Protective Effect in Hemorrhage
Authors: Kulthinee Supaporn , Zhang Ling , Wang Lijiang , Zhao Ting 
Published: May 2024

Introduction: Histone deacetylate inhibition contributes critically to modulating insulin resistance and cardiovascular function. It remains unknown whether inhibition of specific HDAC isoform 4 could improve cardiac function and attenuates inflammatory response and whether HDAC4 inhibition-induced protection is related to irisin. The objective of this study is to investigate whether HDAC4 inhibition induced protective effect against hemorrhage-induced detrimental effects would be diminished by deletion of irisin. Method: Irisin knockout (irisin−/−) mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) Wild type (WT)+Hemorrhage (control) (N=7): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) NVS-HD-1+Hemorrhage (n=7): The same as the group I except that NVS-HD1, a selective HDAC inhibitor (3mg/kg) was infused during resuscitation; III) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; IV) NVS-HD-1 + Irisin−/−+Hemorrhage (n=6): The same as the groups III except that NVS-HD-1 was given to Irisin −/− during resuscitation. Myocardial function and hemodynamics were assessed using echocardiography and femoral artery catheterization, respectively. Cytokine releases from serum were measured using Enzyme-linked immunosorbent assay (ELISA). Histological assessment was performed to determine tissue damage in both myocardium and skeletal muscles. TUNEL was carried out to assess apoptotic signal in tissues. Results: As compared to control group, HDAC4 inhibitor significantly improved the cardiac function and recovery of hemodynamics, which was associated with the decreased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were mitigated by inhibition of HDAC4. However, HDAC4 inhibitor-induced myocardial protection and suppression of inflammation against hemorrhage was lost by genetic deletion of irisin. Conclusion: Selective inhibition of HDAC4 produced protective effects with an improvement in myocardial function and attenuation of inflammation against hemorrhage, which is dependent on irisin. The work is supported by the National Institute of General Medical Sciences (R01GM 141339), United States; the National Heart, Lung, and Blood Institute Grants (R01 HL089405), United States. This is the full abstract presented at the American Physiology Summit 2024 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.
Alteration of the bile acid pool attenuates neuroinflammation in the EAE mouse model of Multiple Sclerosis
Authors: Comiskey Shane , Qazi Aisha , Calzadilla Nathan , Eathara Abhijith , Natarajan Anbazhagan Arivarasu , Saksena Seema , K Dudeja Pradeep 
Published: May 2024

Bile acids are critical signaling molecules that mediate gut crosstalk with other organs, including the brain. The primary bile acids, such as chenodeoxycholic acid (CDCA), are synthesized in the liver and modified by gut bacteria to generate secondary bile acids like the 12α-hydroxylated deoxycholic acid (DCA). Bile acids are effciently absorbed in the distal ileum, and recent studies have implicated them in neuroinflammation and the pathophysiology of several neurological diseases such as Multiple Sclerosis (MS). However, the specific effects of different types of bile acids on MS have not been thoroughly investigated. We hypothesize that bile acids differentially affect neuroinflammation and that treatment with cholestyramine (bile acid sequestrant) modulates astrocyte activation in a mouse model of MS. Methods: Primary astrocyte cultures were prepared from 6-10-week-old C57BL/6 mice and incubated with cytokines in the presence and absence of bile acids. The expression of inflammatory and astrocyte activation markers was assessed by real-time qPCR. The effects of blocking bile acid absorption on MS were examined using the established Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS in 8-week-old female mice (C57BL/6). Mice were fed either a standard chow diet or a standard chow diet supplemented with 2% cholestyramine, a bile acid sequestrant, to block bile acid absorption. Statistical significance between groups was determined by an unpaired T-test. Results: Astrocytes treated with cytokines (TNF-α, 10 ng/mL, IL1-β, 10 ng/mL, 24 h) significantly increased the mRNA expression of TNF-α and IL1-β and markers of astrocyte activation, lipocalin 2 (LCN2), and Serpina3n. Co-treatment with cytokines and CDCA but not DCA (50 μM, 24 h) significantly decreased TNF-α (~56%, p<0.01), IL1-β (~40%, p<0.01), LCN2 (~26%, p<.001), and Serpina3n (~44%, p<.001), vs cytokines alone. The taurine-conjugate, TCDCA, also resulted in significant decreases in the expression of TNF-α (~72%, p<0.001), IL1-β (~53%, p<.001), LCN2 (~30%, p<0.05), and Serpina3n (~16%, p<0.01), suggesting an anti-inflammatory effect specific to CDCA and its taurine conjugate on astrocytes. Cholestyramine treatment in EAE mice was associated with significant reductions in the mRNA expression of TNF-α (~40%, p<0.05) and Serpina3n (~30%, p= 0.217) in the frontal cortex of the brain. Together, these data imply that altering the composition of the bile acid pool may be a viable therapeutic strategy for MS patients by attenuating neuroinflammation. University of Illinois at Chicago, JBVMC, Chicago, IL. This is the full abstract presented at the American Physiology Summit 2024 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.