bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Dynamic Genome at Altitude: Mitochondrial DNA Copy Numbers in Acute and Chronic Hypoxia
Authors: Janocha Allison , Novotny Michael , Xu Weiling , Chen Ruoying , Hu Bo , Koch Carl , Tiso Mauro 
Published: May 2024

Mitochondria contain a tiny circular DNA (mtDNA) that encodes components of the electron transport chain, including Complex IV, where over 95% of oxygen is consumed in the process of generating energy. Each mitochondrion contains tens to hundreds of copies of mtDNA, which decrease with aging and disease, but little is known regarding how mtDNA levels change in response to hypoxia. Here we compare samples with different durations and magnitudes of exposure to high-altitude hypoxia: Ethiopian Amhara with >5000 years exposure and the potential for evolved adaptations, Ethiopian Oromo with ~500 years of generations of lifelong acclimatization, and acutely exposed European trekkers with 15 days of abrupt individual acclimatization followed by descent to baseline. Lowland natives of the same ethnicities provide unstressed reference samples. Our previous studies found that Amhara adapted to hypoxia through increased blood flow due to nitric oxide-mediated vasodilation, while Oromo have increased carrying capacity through elevated hemoglobin concentration. We measured mtDNA copy numbers relative to nuclear DNA (mtDNA-CN) in 326 healthy adults: 52 low-altitude Amhara at 1200 m, 113 high-altitude Amhara at 3700 m; 47 low-altitude Oromo at 1700 m, and 105 high-altitude Oromo at 4000 m; and 9 European lowlanders at a baseline of 1300 m, after ascent to 5050 m, and upon return to 1300 m. High-altitude Amhara had 21% higher median mtDNA-CN than their low-altitude counterparts (median (IQR): high-altitude, 363.0 (281.0–427.0); low-altitude, 299.0 (246.1–333.2); p<0.0001), while high-altitude Oromo had 17% lower mtDNA-CN than their low-altitude counterparts (high-altitude, 236.7 (165.2–315.6); low-altitude, 283.7 (216.9–335.6); p=0.01). High-altitude Amhara had significantly higher median mtDNA-CN than high-altitude Oromo (p<.0001). European lowlanders had 44% lower mtDNA-CN after an 13-day ascent to 5050 m (1300 m, 322.5 (262.8–356.4); 5050 m 180.9 (145.1–230.5); p=0.002) that returned to baseline (319.5 (247.3–267.6); p=0.5) after a 6-day descent to 1300 m. These findings further confirm variation in acute and chronic responses to hypoxia, within and across populations. These findings require validation and expansion to address the mechanisms connecting expression of mtDNA copy numbers to oxygen-requiring bioenergetics. This work is supported by the National Heart, Lung, and Blood Institute HL060917 and National Science Foundation BCS-0452326. 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.
Effect of Endothelin-1 on Resting Blood Pressure and the Blood Pressure Response to Hypoxia in Healthy Young Men
Authors: Gonsalves Anna , Baker Sarah , Jacob Dain , Harper Jennifer , Manrique-Acevedo Camila , Limberg Jacqueline 
Published: May 2024

Objectives: Upregulation of endothelin-1 (ET-1) and its receptors have been linked to increases in hypoxic sensitivity of the carotid chemoreceptors and the development of hypertension. As such, chemoreflex sensitization has been shown in pre-clinical models to be attenuated by ET-1 receptor blockade. Herein, we sought to assess a role for ET-1 in the maintenance of resting blood pressure (BP) in healthy young men and determine whether chemoreflex control of BP could be altered by ET-1 blockade. We hypothesized endothelin receptor antagonism with oral bosentan would lower resting BP in healthy young men as well as the acute BP response to hypoxia. Methods: Twenty-four healthy young men (31±5 yrs, 26±3 kg/m2) completed two study visits (control, bosentan) separated by a minimum of 1 week. The nonspecific endothelin receptor antagonist bosentan (62.5 mg) was taken by mouth twice daily for 3 days prior to the second study visit. On each visit, beat-by-beat BP was assessed under 3 inspiratory air conditions: 1) steady-state normoxia (FiO2 0.21), 2) chemoreflex excitation produced by acute, graded hypoxia (FiO2 0.05 – 0.21), 3) chemoreflex inhibition elicited by transient hyperoxia (FiO2 1.00). Results: Oral bosentan treatment resulted in an increase in plasma ET-1 (0.9±0.9 to 1.3±0.6 pg/mL, p=0.004), supporting receptor blockade. Resting diastolic and mean BP were reduced following 3 days of bosentan treatment compared to control (diastolic: 73±5 to 69±7 mmHg, p=0.007; mean: 93±7 to 88±7 mmHg, p=0.005) with no change in systolic BP (p=0.507). Notably, the BP response to both acute hypoxia (-0.48±0.38 to -0.25±0.31 mmHg/%, p=0.004) and hyperoxia (main effect of bosentan, p=0.025) were attenuated following bosentan. Conclusions: Acute oral bosentan treatment resulted in a reduction in resting BP in healthy young men. The effect of endothelin receptor inhibition with bosentan further attenuated the rise in BP during chemoreflex excitation via acute, graded hypoxia as well as the fall in BP during chemoreflex inhibition (transient hyperoxia). Together these data support a role for ET-1 in control of resting BP in healthy young men, possibly through a chemoreceptor-mediated mechanism. NIH HL130339 (JL), Mayo Clinic Center for Biomedical Discovery (JL, SB). 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.
Limb Position Influences Peripheral Arterial Stiffness Reduction with Reactive Hyperemia
Authors: Jackson Ronald E. , Lima Natalia S. , Sherman Sara R. , Hibner Brooks A. , Clifford Philip S. 
Published: May 2024

Reactive hyperemia can acutely reduce peripheral arterial stiffness. The reduction in peripheral arterial stiffness with reactive hyperemia has been suggested to be flow dependent. However, no previous studies have manipulated the magnitude of hyperemia. We manipulated blood flow by altering limb position to test the hypothesis that a larger increase in blood flow would lead to a greater reduction in peripheral arterial stiffness. Fourteen healthy young adults (5 women; age: 25 ± 5 years; mean ± SD) were included in this study. Peripheral arterial stiffness assessed via brachial to radial pulse wave velocity (PWV) was measured by placing pulse tonometers simultaneously over the brachial and radial arteries. Doppler ultrasound was used to measure brachial arterial blood flow. Arterial blood pressure was continuously monitored via photoplethysmography on the middle finger of the contralateral hand. Reactive hyperemia was performed with the right arm positioned below (≍50°) and above (≍50°) heart level using a rapid-release cuff positioned on the upper arm, inflated to 220 mmHg, sustained for 5 min, then released. Measurements were recorded before cuff inflation and at 5, 15, and 30 min after cuff release. Repeated measures ANOVA revealed a significant condition effect (p<0.01) with peripheral PWV higher with the arm below the heart. There was a significant time x condition interaction (p<.05). At 5-min after reactive hyperemia, peripheral PWV was reduced more with the arm below the heart (9.58 ±1.65 to 7.26 ± 1.51 m/sec) than above the heart (7.08 ± 1.79 to 5.88 ± 1.43 m/sec). Mean arterial pressure did not change across time points (p>0.05). Peak brachial artery blood flow was greater with the arm below the heart (477.37 ± 145 vs 368.64 ± 137 ml/min; p<.001). The results show that reactive hyperemia produces an acute reduction in brachial to radial PWV. The reduction in peripheral arterial stiffness was greater when the arm was below the heart. The mechanism for position-related differences in the reduction in peripheral arterial stiffness with reactive hyperemia may be associated with the magnitude of increase in blood flow. REJ was supported by National Heart, Lung, and Blood Institute (5T32HL134634-04). 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.
A novel target for attenuating T1DM-induced myocardial ferroptosis
Authors: Gawargi Flobater I. , Mishra Paras K. 
Published: May 2024

Background: The DMCM-AHEAD trial showed that lipotoxicity is a distinct feature of diabetic heart failure, which initiates and exacerbates cardiac pathogenesis in diabetic patients. Circulating iron levels are increased in diabetic patients. The combined presence of lipids and iron suggests a predominant role of ferroptosis in diabetes-induced heart failure. However, molecular targets for diabetes-induced myocardial ferroptosis remain unclear. In the T1DM heart, matrix metalloproteinase-9 (MMP9), a protease, is upregulated, and targeted deletion of MMP9 is cardioprotective. Hypothesis: Targeted deletion of MMP9 mitigates T1DM-induced myocardial ferroptosis. Methods and results: We performed in vitro studies on the loss and gain-of-function of MMP9 using human cardiomyocytes (AC16 cells). Overexpression of MMP9 downregulates (-1.55-fold p<0.001) GPX4, a key marker of ferroptosis, while inhibition of MMP9 upregulates (+2.03-fold p<0.001) GPX4 (n=6), suggesting a key role of MMP9 in GPX4 regulation and ferroptosis signaling. To determine the specific role of MMP9 in T1DM-induced ferroptosis, we evaluated ferroptosis markers in the heart (LV) tissue of male Insulin2 mutant (Ins2+/-) Akita (T1DM), littermate euglycemic Ins2+/+ WT, Akita/MMP9 knockout (MMP9KO), and MMP9KO mice (n=3-6). The cardiac levels of Acyl-CoA synthetase long-chain family member-4 (ASCL4), which initiates the formation of lipid peroxides, and divalent metal transporter-1 (DMT1), which increases redox-active iron, were upregulated in the Akita while downregulated in the Akita/MMP9KO hearts (Akita vs WT: ASCL4: +1.42-fold p<0.05, DMT1: +1.34-fold p<0.05; Akita/MMP9 vs Akita: ACSL4: -1.46-fold p<0.05, DMT1: -1.03-fold p<0.05). Furthermore, cardiac levels of Ferritin-Light Chain (FLC), which stores iron to suppress ferroptosis, was downregulated in the Akita but upregulated in the Akita/MMP9KO hearts (Akita vs WT: -2.01-fold p<0.01, Akita/MMP9 vs Akita: +1.36-fold p<0.05). These results suggest that upregulation of MMP9 promotes while inhibition of MMP9 mitigates ferroptosis in the T1DM heart. Conclusion: This is the first report to reveal MMP9 as a promising therapeutic target for T1DM-induced myocardial ferroptosis. This work was supported in part by the National Institutes of Health (NIH) Grant R56HL156806 to PKM, and University of Nebraska Medical Center (UNMC) Presidential Graduate Fellowship to FIG. 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.
Physical activity mitigates serotonin and oxidative stress-associated mesenteric arterial endothelial dysfunction in obesity
Authors: Lee Junghoon , Lee Jonghae , Park Yoonjung 
Published: May 2024

Introduction: Serotonin (5-HT) signaling may play a role in modulating vascular endothelial function. Obesity-induced oxidative stress causes the development of cardiovascular disease (CVD). We aimed to investigate the protective effect of voluntary wheel running (EX) on serotonin receptor (5-HT1B) and oxidative stress in the mesenteric artery of obese mice. Methods: Mice were randomly divided into four groups. They were fed a control low-fat diet (LF) or high-fat diet (HF; 45% of calories from fat) and provided with voluntary wheel running (LF-EX or HF-EX) or a sedentary condition. The protein expressions of phosphorylated-endothelial nitric oxide synthase (p-eNOS), 5-HT1B receptor, Akt, and proteins regulating oxidative stress were quantified by Western blot analysis. Statistical comparisons between groups were performed with two-way ANOVA with Fisher’s LSD test. Results: The protein expressions of p-eNOS, 5-HT1B receptor, and p-Akt in HF were lower compared to LF, but EX increased the protein levels ( P < 0.05). NOX2 in HF was higher compared to LF, but EX decreased it ( P < 0.05). SOD1, SOD2, and UCP2 in HF were lower compared to LF, but EX increased the protein levels ( P < 0.05). There was no difference in expressions of Akt, Gαq/11, NOX4, and VDUP1 between groups. Conclusion: Voluntary wheel running improves e-NOS-mediated vascular endothelial function possibly via increased 5-HT1B receptors and reduced oxidative stress, which could mitigate the risk of obesity-induced CVD. This study was supported by grants from the Cardiovascular Research Foundation Asia (#16215 to Y. P.) and the University of Houston (Small Grant Program to Y. P.). 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.
Local Activation of Angiotensin II Type 2 Receptors Improves Microvascular Endothelial Function in Healthy Women With a History Preeclampsia
Authors: Schwartz Kelsey , Jalal Diana , Santillan Mark , Stanhewicz Anna 
Published: May 2024

Women who had preeclampsia (hxPE) have a >4-fold risk for developing cardiovascular disease (CVD) compared to women who had an uncomplicated pregnancy (hxHC). These women demonstrate attenuated vascular endothelium- and nitric oxide (NO)-dependent dilation, secondary to exaggerated angiotensin (ang) II-mediated constriction, following pregnancy but before the onset of CVD. Despite the known dysregulation of ang II-mediated responses postpartum, the role of vasodilatory ang II type 2 receptors (AT2R) in this dysfunction is unknown. We hypothesized that, compared to hxHC, hxPE would have reduced AT2R-mediated dilation and reduced AT2R expression in primary biopsied endothelial cells. We further hypothesized that endothelium- and NO-dependent dilation would be attenuated in hxPE, and that local AT2R activation would improve these responses in hxPE. Nine hxPE (34±7 years, 25±14 months postpartum) and 9 hxHC (35±3 years, 32±12 months postpartum) had 4 intradermal microdialysis fibers placed in the ventral forearm. Sites 1-2 received graded infusions of compound 21 (C21, AT2R agonist; 10−14-10−3mol/L) alone or with L-NAME (NO-synthase inhibitor; 15mM). Sites 3-4 received lactated Ringer’s (control) or 10−11M C21 and underwent a standard local heating (LH) protocol (42°C; 0.1°C·s−1) to assess endothelium-dependent dilation. After full expression of the LH response, 15mM L-NAME was perfused to assess NO-dependent dilation. Red cell flux was measured over each site with laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure) and normalized to maximum (%CVCmax; 28mM SNP+43°C). AT2R protein expression in biopsied venous endothelial cells (n=4/group) was quantified using immunofluorescence. AT2R-mediated dilation (31±8 vs. hxHC: 95±25%CVCmax, p=0.01) and the NO-dependent portion of this response (21±9 vs. hxHC: 64±23%, p=0.04) was reduced in hxPE. AT2R expression in biopsied endothelial cells was attenuated in hxPE (0.59±0.10 vs. hxHC: 0.79±0.07 arbitrary units; p=0.008). hxPE had attenuated endothelium- (79±7 vs. hxHC: 94±9%CVCmax, p<0.001) and NO-dependent dilation (55±11 vs. hxHC: 71±13%; p=0.01) responses to LH. Local AT2R activation augmented endothelium- (92±11%CVCmax vs. control; p=0.02) and NO-dependent (78±12% vs. control; p<0.001) dilation in hxPE but had no effect in hxHC (all p>0.05). These data suggest that reductions in AT2R-mediated dilation and expression contribute to attenuated endothelial function after preeclampsia. Furthermore, AT2R activation may improve endothelial function through NO-dependent mechanisms in women who have had preeclampsia before the onset of CVD. Internal Funds. 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.
Resistance-Exercise-Induced Circulating Factors on Damaged Skeletal Muscle Tissue Proteome in Young Untrained Men
Authors: Jiwan Nigel , Levitt Danielle , Appell Casey , Luk Hui-Ying 
Published: May 2024

Recovery from muscle damage is tightly orchestrated by multiple physiological processes that can be altered by circulating factors (e.g., cytokines, growth factors) and intracellular signaling pathways (e.g., autophagy). Our previous studies have demonstrated that resistance exercise (RE)-induced circulating factors alter the expression of intramuscular cytokine mRNA and autophagic and myogenic markers in exercise-induced skeletal muscle damage (EIMD). However, the global effects of these circulating factors on damaged muscle are largely understudied. Purpose: To identify global changes in the proteome and functional pathways in skeletal muscle when EIMD is followed by an upper body RE-induced circulating milieu. Hypothesis: RE-induced circulating factors alter protein expression profile in damaged muscle. Methods: Vastus lateralis samples from 3 men included in the parent study were utilized for this report. Untrained men (age: 23 ± 5yr; height: 181.6 ± 5.9cm; weight: 86.0 ± 15.8kg) completed 2 identical bouts of maximal unilateral eccentric knee extensions for 8 sets of 10 repetitions, which were immediately followed by either heavy upper body RE to induce changes in circulating factors (EX) or 20 min seated rest (CON). Muscle samples from the damaged leg at 24h were used to compare between conditions. The total number of proteins was measured using LC-MS/MS. Bioinformatic analyses were performed via Qiagen Ingenuity Pathway Analysis software. For identifying enriched biological processes and functions, proteins had to have at least 1.0-fold differential expression with an FDR-adjusted significance level < 0.05. Z scores were calculated to predict changes in biological functions. Results: A total of 900 proteins were identified. For EX, 79 proteins were downregulated, and 15 were upregulated compared to CON at 24h. Pathway analyses demonstrated that for EX, there was decreased activation in acute phase response signaling, liver X receptor/retinoid X receptor activation, nitric oxide production and reactive oxygen species in macrophages, and neutrophil extracellular trap signaling pathways compared to CON. In addition, for EX, there was an increase in macrophage IL-12 signaling and production than CON. Conclusion: RE-induced changes in circulating factors modulated pathways associated with the immune response and cytokine signaling in untrained men. Given that immune response is critical for recovery from muscle damage, these results highlight the potential role of RE-induced circulating factors (e.g., hormones, growth factors, etc.) which could play a role in mediating muscle recovery. 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.
Adropin Treatment Restores Cardiac Function and Metabolic Flexibility in Diabetic Cardiomyopathy
Authors: Mushala Bellina , Stoner Michael , McMahon Brenda , Vandevender Amber , Mullett Steven , Gelhaus Stacy , Jurczak Michael 
Published: May 2024

Background: Diabetic cardiomyopathy (DCM) is a major complication of diabetes, and has been recognized as a cause of heart failure independent of other common risk factors. Metabolic inflexibility is a hallmark feature, where increased free fatty acid availability and decreased myocardial glucose uptake lead to an over-reliance on fatty acid oxidation, reducing cardiac work effciency. Energetic ineffciency in diabetic hearts may have profound implications for cardiac function under conditions of increased workload, and therefore therapeutic approaches are warranted. Adropin is a liver- and brain-secreted peptide hormone shown to regulate fuel metabolism in the heart. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity, insulin resistance, and impaired glucose tolerance. Our lab recently showed that acute adropin treatment restores glucose oxidation activity in the hearts of prediabetic obese mice. However, the effects of chronic adropin exposure in the heart remains unknown. Hypothesis: We hypothesize that adropin treatment will exhibit beneficial effects on cardiac fuel metabolism that may lead to long-term improvements in functional output. Methods: We used a preclinical model of DCM to investigate the effects of long-term adropin treatment on cardiac structural and metabolic remodeling. Mice were treated with adropin daily for four weeks, and subjected to echocardiography, glucose tolerance tests, histopathology, RNA-sequencing, and metabolomics. Results: We report that long-term adropin treatment restores normal cardiac structure and metabolic function in the diabetic heart, by inhibiting flux of non-oxidative glycolytic intermediates into the hexosamine biosynthetic pathway. Conclusions: Our findings highlight the therapeutic potential of adropin signaling to attenuate cardiac remodeling in DCM. The project described was supported by NIDDK 1F31DK134089 and NHLBI R01HL147861. 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.