bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Heat Exposure on Inflammation and Platelet Activity in Adults with Heart Disease
Authors: Sardar Soha , Barry Hadiatou , Welman Mélanie , Mornas Adèle , Lordkipanidzé Marie , Gagnon Daniel
Published: May 2024

INTRODUCTION: Extreme heat events are associated with a greater risk of cardiovascular mortality, especially in adults with pre-existing heart disease. The pathophysiological mechanisms mediating these relationships remain unknown. One proposed mechanism, supported by pre-clinical studies employing heat stroke models of severe body hyperthermia, is that heat exposure causes an inflammatory response leading to platelet activation and clot formation. It remains unknown if milder body hyperthermia, such as the one experienced during exposure to a hot environment, elicits an inflammatory response and/or increases platelet activity in adults living with heart disease.OBJECTIVES & HYPTOHESES: To assess whether exposure to a hot and humid environment (1) increases circulating concentrations of inflammatory cytokines and (2) induces platelet activation in adults with heart disease.METHODOLOGY: Adults living with coronary artery disease (67±8 years; 13M/2F) sat within a climate chamber maintained at 38°C and 50% humidity for 3h. Core (rectal) and skin temperatures were measured continuously. Blood samples were drawn before and 2.5h into heat exposure. The blood samples were analyzed for IL-6, IL-8, IL-18, TNFα and IL-1β (multiplexed bead-based immunoassay). Platelet aggregation was measured by impedance (Multiplate assay) induced with ADP (6.5 μM), TRAP (15 μM) and collagen (1.5 μg/ml). The total-thrombus analysis system (T-TAS, PL-CHIP) was used to measure thrombus onset time and total thrombogenicity.RESULTS: Core and skin temperatures increased by 0.35 ± 0.24°C and 4.85 ± 0.84°C, respectively (p<0.05). There were no changes (Δpost-pre) in IL-6 (0.31 ± 1.91 pg/ml, p=0.60), IL-18 (-10.29 ± 21.01 pg/ml, p=0.16), IL-8 (1.10 ± 2.39 pg/ml, p=0.18), TNFα (-1.12 ± 4.10 pg/ml, p =0.39), or IL-1β (0.53 ± 2.36 pg/ml, p=0.48) during heat exposure. Moreover, heat exposure did not increase platelet activation in response to ADP (-8.31 ± 33.70 U, p=0.34), TRAP (16.19 ± 36.54 U, p=0.10), or collagen (-9.19 ± 30.31 U, p=0.24). Lastly, there was no change in thrombus onset time (2.18 ± 37.31 s, p=0.850) or total thrombogenicity (2.8 ± 168.7 PL-AUC, p=0.90).CONCLUSION: These results suggest that inflammation predisposing to thrombus formation may not contribute to the greater cardiac risk associated with short-term exposure to humid heat.

Canadian Institutes for Health Research.

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.
TRPV4-driven Regulation of miR-146a Expression in Macrophages and in a Mouse Model of Atherosclerosis
Authors: Dutta Bidisha , Mahanty Manisha , Rahaman Shaik O.
Published: May 2024

MicroRNAs (miRs) are small, non-coding RNAs that have emerged as powerful regulators of gene expression. Emerging evidence suggests that miR-146a orchestrates anti-inflammatory/fibrotic processes in numerous cell types. Trpv4 (Transient Receptor Potential subfamily V member 4), a mechanosensitive, calcium-permeant channel/receptor, is expressed in numerous cell types including macrophages. Published work by our group and others show that Trpv4 is activated by a range of soluble and physical stimuli including matrix stiffness and cytokines. In mice, Trpv4 deficiency is associated with altered pressure responses, foreign body response, fibrosis, and inflammation. Previous work by our group and others suggest a pro-inflammatory/atherogenic role for Trpv4. Herein, we tested the hypothesis that Trpv4 regulates the expression of microRNA-146a in macrophages and in a mouse model of atherosclerosis. Our research found a 38% drop in miR-146a expression in macrophages treated with lipopolysaccharide (LPS) on a stiffer polyacrylamide hydrogel compared to a softer one as determined by RNAseq analysis, signifying miR-146a's sensitivity to mechanical factors. Trpv4's presence suppresses the LPS-induced increase of miR-146a in macrophages based on time and dosage. Trpv4 also plays a role in the suppression of miR-146a due to matrix stiffness. Notably, in mice, Trpv4 reduces the increase of macrophage miR-146a caused by a high-fat diet in aortic root regions. Given that matrix stiffening is common in atherosclerosis, this indicates a link between stiffness, Trpv4, and miR-146a. On the mechanism side, Trpv4 affects miR-146a expression not through its promoter methylation or activation of MAPKs, Stat1, AKT, and NFκB. Trpv4 residues 100 to 130 are required for suppression of LPS-induced upregulation of miR-146a. To sum up, Trpv4 appears to inhibit macrophage miR-146a expression through pathways that are distinct from those involving MAKPs/Stat1/AKT or NFκB. Understanding this mechanism could pave the way for new treatments targeting miR-146a to counter inflammatory diseases.

Source of research support: NIH (R01 AI172086) grant to Shaik O. Rahaman.

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.
Mir-146a is required for foreign body response and giant cell formation
Authors: Mahanty Manisha , Dutta Bidisha , Rahaman Shaik O.
Published: May 2024

The implantation of biomaterials or medical devices often leads to the development of a foreign body response (FBR), an inflammatory condition that can lead to implant failure, which may cause harm to or death of the patient. Hallmarks of the FBR include accumulation of macrophages and destructive foreign body giant cells (FBGCs), and development of fibrous scar tissue encompassing the implant. There are no effective medical treatments for FBR, although improved fundamental understanding of the molecular mechanisms underlying the development of FBR may lead to novel strategies for the amelioration of FBR. MicroRNAs (miRs) are endogenous, small, non-coding RNAs that have emerged as powerful regulators of gene expression in numerous cellular processes including macrophage activation, inflammation, and fibrosis. In this research, we tested the hypothesis that specific miRs play a crucial role in regulating the FBR to biomaterials. In our subcutaneous implantation mouse model, we found that: 1) miR-146a expression levels decreased in the implant-adhered tissues, and the decrease correlated with increased macrophage accumulation, FBGC formation, and collagen accumulation; and 2) miR-146a deletion in mice exacerbated in vivo macrophage accumulation, FBGC formation, and collagen accumulation. In our in vitro model, we found that deficiency of miR-146a function exacerbated key macrophage functions including adhesion on stiff matrix, and FBGC formation in primary mouse macrophages. In essence, our findings suggest that miR-146a might act as a suppressor of FBR. We expect that the results of this study may provide invaluable information and insight regarding the molecular mechanisms mediating the FBR to biomaterials, which may lead to the development of a novel microRNA-based therapeutic strategy for the amelioration of the poorly understood FBR to biomaterials.

NIH (R01 AI172086) grant to Shaik O. Rahaman.

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.
Effects of Acute Melatonin Supplementation on Cardiovascular Variables During Sympathetic Stimuli in Healthy Young Individuals
Authors: Skillett Sarah , Song Jiwon , Buelow Alexander A. , Matney Jacob E. , Mixon Chris , Akbari Amir , Stanford Matt
Published: May 2024

Melatonin supplementation has displayed antihypertensive and antioxidant functions in animals and clinical populations. While the exact mechanisms are unknown, animal studies have indicated melatonin may inhibit sympathetic responses by inhibiting vascular α-receptors. However, these effects are untested in humans. PURPOSE: To determine if acute melatonin supplementation alters vascular responses to sympathetic activation caused by mild hypovolemia at rest and during rhythmic exercise in healthy humans. METHODS: 14 healthy young adults (25±1 years, 6 females, tested in days 1-7 of menstrual cycle) participated in a randomized, single blind, crossover protocol. 5 mg of melatonin (MEL) or placebo (PLA) (mint water, mimics flavor of melatonin spray) were given as a sublingual spray 30 minutes before data collection to allow for peak absorption. Forearm blood flow (FBF, doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography) were continuously measured during 5 min of supine rest, 2 min of −20mmHg lower body negative pressure (LBNP, causes simulated hypovolemia), 7 minutes of rhythmic handgrip exercise at 20% maximal effort, with minutes 5-7 having LBNP superimposed (Ex+LBNP). Each event was separated by 10 min of quiet rest. Forearm vascular conductance (FVC, FBF/MAPx100mmHg) was calculated. Paired t-tests were performed to compare data between conditions, significance was set as p ≤0.05. RESULTS: Data are presented as Δ% mean ± SD. No significant differences were found with small effect sizes for FBF (PLA:-23.64±22.46 vs. MEL: -34.14±27.17, p=0.33, r=0.18) and FVC (PLA:-22.97±24.16 vs. MEL:-32.98±28.01, p=0.36, r=0.17) from rest to LBNP. There were also no significant differences found, with small effect sizes for FBF (PLA:996.61±1385.63 vs. MEL: 643.24±588.87, p=0.30, r=0.19) and FVC (PLA:770.60±1071.85 vs. MEL:513.45±478.07, p=0.33, r=0.18) from rest to exercise. Lastly, no significant differences were found with small effect sizes for FBF (PLA:4.41±22.48 vs. MEL:4.57±20.08, p=0.98, r=0.01) and FVC (PLA:2.75±21.16 vs MEL:2.93±19.79, p=0.88, r=0.03) from exercise to exercise with LBNP. CONCLUSION: Our data indicates that melatonin does not alter vascular responses with sympathetic stimuli caused by mild hypovolemia, exercise, and combined hypovolemia and exercise. Thus, any vascular effects of melatonin supplementation are not likely caused by inhibition of alpha receptors in healthy humans and the observed improvements in clinical populations are likely attributable to other mechanisms.

Non-applicable.

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.
Modulation of Cardiac Ryanodine Receptors by Chloride Intracellular Ion Channel 2
Authors: Sanghvi Shridhar , Sridharan Divya , Bhachu Harmeet , Sayed Nazish , Khan Mahmood , Singh Harpreet
Published: May 2024

Pathogenic variants of the Chloride intracellular ion channel 2 (CLIC2) are implicated in hypertrophic cardiomyopathy (HCM), a diverse heart condition leading to arrhythmic sudden cardiac death and heart failure. CLIC2 is a unique class of metamorphic protein, related to the enzymatic glutathione s-transferase family and form functional ion channel. Artificial bilayer studies have shown that CLIC2 negatively modulates the activity of cardiac ryanodine receptor 2 (RyR2), implicating the sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ release. However, the subsequent consequences of RyR2 and CLIC2 interaction in cardiac physiology remains unknown. Therefore, we ablated clic2 in human induced pluripotent stem cell (hiPSC) line using the CRISPR-Cas9 system and performed cardiomyocyte differentiation. clic2−/− hiPSC-derived cardiomyocytes (hiPSC-CMs) showed altered electrophysiological properties leading to impaired excitation-contraction coupling. clic2−/− hiPSC-CMs showed an increase in beat rate and field potential duration by 143.49±5.96% and 162.43±5.82%, respectively, whereas conduction velocity and spike amplitude decreased by 43.81±2.22% and 43.32±3.54%, respectively compared to WT hiPSC-CMs. Additionally, action potential duration measurements of clic2−/− hiPSC-CMs showed a decrease in APD30, APD50, and APD90 by 74.42%, 65.19%, and 66.46%, respectively compared to WT hiPSC-CMs. Moreover, clic2−/− hiPSC-CMs showed altered Ca2+ handling, with a decrease in peak amplitude (57.07±2.25%) and duration (38.29±1.30%) compared to the WT hiPSC-CMs. The caffeine induced Ca2+ release in clic2−/− hiPSC-CMs, attributed to the SR/ER Ca2+ overload which decreased by 72.19±3.51% compared to WT hiPSC-CMs. Transcriptomics analysis of clic2−/− hiPSC-CMs revealed 223 transcripts with significant changes in expression levels (89 upregulated and 134 downregulated), implicating CLIC2 in hypertrophy cardiomyopathy, dilated cardiomyopathy, and other heart diseases. Furthermore, the protein expression of CLIC2 increases in end-stage failing human heart samples compared to the non-failing heart. In conclusion, our study sheds light on the novel role of CLIC2 in the regulation of cardiac (patho)physiology.

National Institutes of Health (NIH) (HL133050, and HL157453); American Heart Association-Transformational Project Award; National Center for advancing translational sciences (TR004178, understudied proteins and druggable targets) (HS). Presidential Predoctoral Fellowship; Margaret T. Nishikawara Merit Scholarship Endowment in Physiology; Graduate School’s Alumni Grants for Graduate Research and Scholarship Program, The Ohio State University (SS).

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.
Does Zn deficiency promote kidney damage?
Authors: Hasrat Khanzada , Wenegieme Tara-Yesomi , McMichael Kelia , Rockwood Jananie , Waite Aston , Barrett Hannah , Nshuti Adeline
Published: May 2024

Background: Chronic kidney disease (CKD) impairs the kidneys’ ability to filter blood. End stage renal disease (ERSD), which is characterized by irreversible kidney fibrosis, progresses from CKD. Significant events in kidney fibrosis include the transformation of activated renal cells into myofibroblasts which can be detected by the abundance of ⍺-SMA, and the subsequent deposition of Extracellular Matrix Proteins (ECM). Previous studies have shown CKD patients are zinc deficient which is a critical micronutrient that is responsible for supporting several physiological processes in the body. Based on these findings, we hypothesize that zinc deficiency promotes kidney fibrosis. Experimental Design: To investigate the role of zinc in renal damage, wild type, adult mice (C57BL/6J) were on either a Zn-adequate (ZnA) or a Zn-deficient (ZnD) diet for 10 weeks. To examine the effects of Zn repletion (ZnR), at week 8, a subset of ZnD mice was returned to the ZnA diet. At the end of the study, kidneys were harvested and processed for immunohistochemistry to assess kidney fibrosis. Results: While ZnD mice had greater expression of ⍺-SMA, enhanced ECM deposition was not observed. However, increased ECM deposition was present in ZnR mice. Conclusion: Even though ZnD promotes activation of ECM producing cells, renal fibrosis was absent. Significance: These findings indicate a complicated interplay between Zn homeostasis and kidney fibrosis that warrants further investigation.

Funding: R21 DK119879, R01 DK-133698.

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.
The gut microbiome regulates thermogenic performance in high-altitude deer mice
Authors: Scott Graham R. , Zucker Emma A. , MacPherson Jess , Bucking Carol
Published: May 2024

High altitude is one of the most extreme environments inhabited by endotherms, where cold temperatures demand high rates of thermogenesis to maintain body temperature (Tb) but hypoxia constrains aerobic metabolism. Recent findings suggest that the gut microbiome contributes to whole-body thermogenesis, but its significance for coping in cold environments remains poorly understood. We hypothesized that the gut microbiome contributes to adaptive increases in thermogenic performance in deer mice native to high altitude. Mice from populations native to high altitude and low altitude were born and raised to adulthood in common lab conditions. Adults from both populations were then acclimated to warm (25°C) normoxia or cold (5°C) hypoxia (12 kPa O2) for 6 weeks, and a subset of mice in each group were treated with antibiotics to disrupt the gut microbiome. Thermogenic endurance was then measured as the duration that Tb could be maintained during acute cold challenge. Antibiotic treatment strongly diminished thermogenic endurance in highlanders, but led to only minor reductions in thermogenic endurance in lowlanders. These differences could not be fully explained by impairments in aerobic heat production by host thermogenic tissues, because antibiotic treatment had only modest effects on cold-induced increases in O2 consumption rate and the abundance of UCP-1 protein and oxidative phosphorylation complexes in brown adipose tissue. Therefore, our findings suggest that the gut microbiome plays an increased role in regulating thermogenesis in high-altitude deer mice, and that changes in host-microbe interactions contribute to high-altitude adaptation.

Funded by NSERC 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.
Molecular organization of adrenergic and noradrenergic neurons in the mouse ventrolateral medulla
Authors: Stornetta Daniel , Schwalbe Dana , Abraham-Fan Ruei-Jen , Souza George , Jalil Maira , Crook Maisie , Campbell John
Published: May 2024

Catecholaminergic neurons in the ventrolateral medulla (VLM) regulate many important aspects of physiology, including the sympathetic control of blood pressure, glucose homeostasis, immune function, and the neuroendocrine responses to inflammation and stress. Previous studies have parsed catecholaminergic VLM neurons into distinct sub-populations based on neurochemical content, connectivity, and distinct response to the activation of autonomic reflexes. However, there is no consensus for the molecular organization of catecholaminergic neurons. In this study, we used high-throughput single nuclei RNA sequencing combined with anatomically- and genetically-targeted cell-sorting of spinally-projecting and catecholaminergic neurons to systematically characterize C1 and A1 neurons in the mouse VLM. Our results, based on an analysis of 894 catecholaminergic neurons derived from a dataset of 114,805 single-nuclei transcriptomes, indicate that the VLM contains 7 molecularly distinct subpopulations of catecholaminergic neurons, including 5 adrenergic subtypes and 2 noradrenergic subtypes identified by the expression of enzymes involved in the production of catecholamine ( Th, Dbh) and the vesicular transporters for glutamate ( Slc6a17) and noradrenaline ( Slc6a2). Neurons with projections to the spinal cord were present in 4 of 5 adrenergic cell clusters, and 1 noradrenergic cell cluster. We histologically verified two novel markers of the adrenergic ( Hk2) and noradrenergic ( Eya1) neurons using RNA fluorescent in situ hybridization. Hk2 expression was found primarily in Dbh+ neurons in the rostral VLM, including both bulbospinal and non-bulbospinal neurons, as well as majority of Pnmt+ neurons in the rostral VLM and C2/C3 regions. Eya1 co-localized with Dbh and Slc6a2 consistently in the caudal VLM, aligning with the location of the A1 neurons, whereas Eya1 signal was diffuse in the rostral VLM. Collectively, this shows that Hk2 expression is enriched in adrenergic neurons as judged by conventional criteria irrespective of the cell's location in the medulla, whereas Eya1 is enriched in brainstem noradrenergic neurons and provides a marker for A1 neurons. These data show molecularly distinct adrenergic and noradrenergic neurons are spatially intermixed in the VLM, and provides novel gene markers for distinct subtypes of catecholaminergic neurons that can be used to dissect the function in future studies.

This work was supported by National Institute of Health (NIH) R01 HL148004 to SBGA; and R01 HL153916, Pathway to Stop Diabetes Initiator Award 1-18-INI-14, and UVA 3Cavaliers grant to JNC.

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.
Muscle Sympathetic Action Potential Firing Patterns Following Intranasal Insulin Administration in Healthy Adults
Authors: McMillan Neil J. , Jacob Dain , Shariff Brian , Harper Jennifer , Gonsalves Anna , E. Foster Glen , Manrique-Acevedo Camila
Published: May 2024

Objective: Systemic insulin increases muscle sympathetic nervous system activity (MSNA) in healthy adults by augmenting firing frequency of medium-sized sympathetic action potentials (AP) and recruiting previously latent, larger axons. Whether these neural coding patterns are due to central or peripheral effects of insulin is unclear. We examined the impact of elevated central insulin on AP firing patterns in healthy adults. We hypothesized intranasal insulin administration, which increases central insulin levels, would increase MSNA via elevated firing frequency of APs and recruitment of previously latent, larger axons. Methods: Ten participants were assigned to time control [TC, n=6 (3M/3F)] or 160 IU of intranasal insulin [n=4 (3M/1F)] administered over 5 min. MSNA (fibular microneurography) was assessed at baseline and for 30 min following insulin administration. Sympathetic APs were identified using a matched mother wavelet and continuous wavelet transform. APs were divided into the proportion of those firing in small, medium, or large amplitude clusters. AP firing frequency, percent of APs firing within an MSNA burst (synchronous), and the probability of clusters firing more than once within an MSNA burst were identified. Data are reported as median (interquartile range). Results: MSNA burst frequency increased 15 min after intranasal insulin administration [24(20) to 31(23) bursts/min, p=0.03]. At this time, the percent of synchronous APs [72(27) to 90(24)%, p=0.02] and the probability of medium-sized AP clusters firing more than once within an MSNA burst [13(14) to 19(17)%, p=0.03] increased. No changes in MSNA burst frequency [23(14) to 25(13) bursts/min, p=0.27], percent of synchronous APs [74(15) to 75(34), p=0.48], nor firing probability of medium-sized AP clusters [6(12) to 8(7)%, p=0.97] occurred in TC. The total number of detected clusters did not change in either group (p>0.05). Conclusions: Intranasal insulin increases MSNA burst frequency due to a higher percent of synchronous APs, particularly medium-sized AP clusters; however, we did not observe recruitment of latent, larger axons. These exploratory data highlight potential differences in the sympathetic response to central versus peripheral insulin exposure in healthy adults.

CAFNR Joy of Discovery (JKL, JP).

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.
β-Adrenergic Receptor Blockade Augments Sympathetically Mediated Vasoconstriction during Hypoxia in Healthy Young Adults
Authors: Jacob Dain , Shariff Brian , Bond Braden , Boyes Natasha , Harper Jennifer , Bostick Brian , Limberg Jacqueline
Published: May 2024

Objective: Vascular tone is dictated by the net balance of vasodilatory and vasoconstrictor influences. During hypoxia, systemic sympathetic vasoconstrictor activity is increased but peripheral vasodilation prevails — suggesting vasodilatory factors outweigh sympathetically-mediated vasoconstrictor influences in the healthy state. Given vascular β-adrenergic receptors contribute to hypoxic vasodilation, we hypothesized pharmacological blockade of β-adrenergic receptors would augment the vasoconstrictor response to acute sympathetic activation during hypoxia. Methods: Thirteen young healthy participants (5F/8M, 27±7 yr, 25±3 kg/m2) completed two study visits randomized and blinded to oral placebo or propranolol (1mg/kg, NCT05256069). On each visit, participants completed two trials: 1) 10-min normoxia (0.21 FiO2, 98±0% SpO2) followed by sympathetic activation via a 2-min normoxic cold pressor test (CPT); 2) 5-min steady-state hypoxia (0.10±0.01 FiO2, 81±1% SpO2) followed by a 2-min hypoxic CPT. Forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed. FBF was normalized for mean BP (forearm vascular conductance, FVC). A change in FVC from steady-state to the last 1-min of CPT was calculated (ΔFVC = CPT − steady-state) and expressed as a percent change (%FVC = ΔFVC/steady-state x 100). Results: The vascular response to sympathetic activation (CPT) was unaffected by hypoxia under placebo conditions (normoxia: -34±21%; hypoxia: -29±32%, p=0.33). In contrast, following β-adrenergic blockade with oral propranolol, sympathetically-mediated vasoconstriction was augmented during hypoxia (normoxia: -29±30%; hypoxia: -40±27%, p=0.04). Conclusion: β-adrenergic receptor blockade augments the vasoconstrictor response to acute sympathetic activation during hypoxia in a mixed-sex cohort. These preliminary data indicate functional β-adrenergic receptors are required to restrain sympathetically-mediated vasoconstriction during hypoxia. Based on data supporting sex-related differences in adrenergic control of vascular tone, future work will seek to stratify results by sex.

Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL).

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 Peripheral Versus Central Insulin on Cerebrovascular Compliance in Healthy Young Adults
Authors: Shariff Brian , Shoemaker Leena , Pipkins Aubrey , McMillan Neil J. , Jacob Dain , Gonsalves Anna , Harper Jennifer
Published: May 2024

Objective: Vascular compliance is an essential component of cerebral blood flow regulation. Prior work has shown cerebral vasodilation (elicited by hypercapnia) reduces cerebrovascular compliance (Ci); however, this work has yet to be translated to other vasoactive compounds. Insulin has important vasodilatory effects in the peripheral circulation, but less is known about the role of insulin in cerebrovascular control. Herein, we hypothesized both peripheral (intravenous) and central (intranasal) insulin administration would increase indices of cerebral blood flow and reduce Ci in healthy young adults. Methods: Twenty-five healthy young adults (8 female; 26±7 yrs, 25±3 kg/m2) were assigned to two separate protocols (NCT05244694, NCT05153395). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound) was measured at baseline and under two study conditions: 1) at the end of a 60 min hyperinsulinemic euglycemic infusion, and 2) 60 min following 160 IU of intranasal insulin. Indices of Ci were calculated using a modified Windkessel model applied to blood pressure (finger photoplethysmography) and corresponding MCAv waveforms collected over a 5-min period (10 waveforms) at baseline and during the aforementioned insulin conditions. Results: Blood glucose remained unchanged throughout both protocols (both p>0.05). MCAv was maintained over time under both insulin conditions (protocol 1: 60±13 to 62±17 cm/s, p=0.635; protocol 2: 58±9 to 53±14 cm/s, p=0.146). In contrast, Ci decreased (0.00028±0.00010 to 0.00021±0.00007 cm/s/mmHg, p=0.010) from baseline during peripheral (intravenous) insulin administration. No change in Ci (0.00049±0.00025 to 0.00040±0.00018 cm/s/mmHg, p=0.189) were observed following intranasal insulin administration. Conclusions: Contrary to our hypothesis, there was no effect of peripheral or central insulin administration on resting MCAv in healthy young adults. However, intravenous (but not intranasal) insulin reduced Ci by approximately 25% from baseline values. These findings advance our understanding of cerebrovascular control mechanisms during insulin exposure and provide the opportunity to extend this work to diseased states characterized by insulin resistance, including diabetes.

CAFNR Joy of Discovery (JKL, JP).

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.
Reprogramming cardiac macrophages with circular RNAs to attenuate post-MI adverse remodeling
Authors: Jung Mira , Schmidt Arne , Sansonetti Marida , Al Soodi Bashar , Thum Thomas
Published: May 2024

Cardiac macrophages (cMφ) play a critical role in cardiac remodeling following myocardial infarction (MI). Reprogramming cMφ towards a favorable wound-healing phenotype is emerging as a promising therapeutic strategy for MI patients. Circular RNAs (circRNAs) are a unique class of non-coding RNAs with high stability and abundance, making them attractive therapeutic targets. However, the role of circRNAs in cMφ physiology during heart failure (HF) progression is poorly understood. To identify circRNAs as key regulators of cMφ dynamics, we performed RNA sequencing and bioinformatics analysis on heart biopsies from healthy donors and patients with ischemic HF. We identified a promising circRNA, circMJ1, as a regulator of Mφ polarization and inflammatory response. CircMJ1 was highly expressed in cMφ and its expression was associated with cMφ polarization. Knockdown of circMJ1 significantly inhibited inflammatory signaling pathways in cMφ and reduced the secretion of pro-inflammatory cytokines. The secretome from circMJ1-silenced cMφ (circMJ1-KD cMφ) also significantly suppressed the migration of cardiac fibroblasts and apoptosis of cardiomyocytes. To further assess the therapeutic effcacy of circMJ1-KD Mφ in cardiac remodeling in the context of MI, we employed a novel multicellular 3D ex vivo model, called living myocardial slices (LMS). We applied circMJ1-KD Mφ to both rat LMS subjected to cryo-injury mimicking MI and HF patient-derived LMS. Interestingly, co-culture with circMJ1-KD Mφ demonstrated a remarkable reduction in inflammation and fibrosis, alongside notable improvement in cardiac function in both cryo-injured rat LMS and HF patient-derived LMS. Overall, our findings reveal circMJ1 as a crucial "switch" for Mφ dynamics and suggest the therapeutic potential of engineered circMJ1-silenced Mφ to improve post-MI healing.

Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) –465131031.

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.
No sex differences in the cardiac responses during high altitude sojourn to 4300 m
Authors: Crew Molly , Burkhart Abigail , Steffen Carolyn , Smith Denise , Brutsaert Tom , Day Trevor , Lefferts Wesley
Published: May 2024

Ascent to high altitude reduces oxygen availability and provokes compensatory cardiovascular responses. Females may exhibit attenuated hypoxic ventilatory responses compared to males, which could subsequently exaggerate the cardiovascular response to high altitude among females. The purpose of this study was to examine sex differences in cardiac responses during high altitude sojourn in young, healthy males and females. We hypothesized that females would exhibit a greater reduction in arterial oxygen saturation, and greater cardiac dysfunction compared to males. 17 healthy adults (8 males, 24±4 yrs, BMI 25.7±3.1 kg/m2; 9 females, 23±4 yrs, BMI 24.5±3.0 kg/m2) underwent cardiac assessment via echocardiography at 1400 m and after an 8-day ascent to 4300 m. Left ventricular (LV) systolic function was assessed via ejection fraction and fractional shortening. Diastolic function was assessed as the ratio between early and late mitral filling velocities (E:A ratio). The subendocardial viability ratio (SEVR) was derived from carotid tonometry, and carotid pressure waves were integrated with echocardiography derived measures of left ventricular ejection to estimate a left ventricular pressure-volume loop and calculate stroke work. Ascent from 1400 m to 4300 m resulted in reduced end-tidal CO2 (-Δ8±3 [males], -Δ8±2 mmHg [females], p<0.001), oxygen saturation (-Δ11±3 [males], -Δ11±5 % [females], p<0.001), and LV fractional shortening (-Δ7.9±7.5% [males] -Δ1.0±6.4 % [females], p=0.028) in both groups. Despite greater stroke work among males (p=0.002), high altitude-induced changes were not statistically different compared to females (+Δ35±184 [males], +Δ3±113 mL/mmHg [females]). Changes in LV ejection fraction (-Δ1.9±14.4 [males], -Δ1.5±18.7 % [females]) mitral E:A (-Δ0.33±0.53 [males], -Δ0.09±0.64 au [females]), and SEVR (-Δ0.06±0.33 [males], +Δ0.15±0.20 au [females]) from 1400 to 4300 m were not statistically different between sexes. Ascent from 1400 to 4300 m decreased end-tidal CO2, arterial oxygen saturation, and select metrics of LV systolic function (e.g., fractional shortening), but LV diastolic function, stroke work, and SEVR was preserved in both males and females. We observed no apparent sex differences in the effects of 8-day sojourn to 4300 m on arterial oxygen saturation, or cardiac systolic and diastolic function. Additional research is necessary to confirm these results in the context of longer-term altitude exposure and acclimatization, and in older populations (middle-aged and older adults).

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.
Fasting Metabolic Profiles are Cell-Autonomous in Elephant Seal Primary Muscle Cells
Authors: Allen Kaitlin , Crocker Daniel , Vazquez-Medina Jose Pablo
Published: May 2024

Northern elephant seals ( Mirounga angustirostris) undergo prolonged terrestrial fasts during energetically intensive life stages including breeding, molting, and postnatal development. Fasting-tolerant vertebrates generally extend the second phase of fasting, during which body mass declines but homeostasis is preserved through reliance on lipid fuel sources and sparing of body protein stores. In elephant seals, the postnatal fast coincides with development of the extensive body oxygen stores required to support extended breath-hold diving, as well as an increased capacity for apnea-related metabolic suppression. Studies in grizzly bears, another large-bodied fasting-tolerant mammal, have identified both serum-derived and intrinsic cellular regulation of the adipocyte metabolic phenotype. However, it is unknown whether these mechanisms extend across species, tissue, or fasting type (active vs inactive). Thus, we derived proliferative primary skeletal muscle cells (myoblasts) from weaned elephant seal pups; biopsies that yielded cells were collected at both early (~1 week) and late (~8 weeks) points in the postnatal fast. We found that total ATP production rate was greater in myoblasts collected from animals late in the fast (27% increase over early, p=0.08). Throughout the fast, myoblasts relied predominantly on glycolytic rather than oxidative ATP production (p<0.001), and this reliance increased as the fast progressed (p<0.014). Together, these data suggest that metabolic reliance is at least partially cell-autonomous in elephant seal myoblasts.

KNA is supported by an NSF Graduate Research Fellowship (DGE 1752814 & 2146752) and a UC Berkeley Fellowship. JPV-M is supported by a NIH/NIGMS grant (R35GM146951). Research was funded by UC Berkeley startup funds and the Winkler Family Foundation.

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 Renin Angiotensin System Inhibition on Renal Function in Fructose-induced Salt Sensitive Blood Pressure
Authors: Pitpitan Rebekah , Siddiqui Sharif , Boychev Boycho , Rossi Noreen
Published: May 2024

Combined dietary intake of fructose with high salt at levels comparable to that in the upper quintile of western population increases blood pressure, decreases glomerular filtration rate, and results in albuminuria and insulin resistance. We tested the hypothesis that chronic treatment with either an angiotensin converting enzyme inhibitor (enalapril) or angiotensin receptor blocker (losartan) will preserve glomerular filtration rate (GFR) and reduce albuminuria. Sprague Dawley rats of both sexes were instrumented with telemetry. After a baseline period on glucose+0.4% NaCl, rats were assigned to the following groups: 20% glucose+0.4%NaCl treated with vehicle (GNS+V) or 20% fructose+4% NaCl and treated with either vehicle (FHS+V), losartan 0.42 mg/kg/hr by osmotic minipump (FHS+L) or enalapril 0.21 mg/kg/hr (FHS+E). The doses of losartan and enalapril were chosen to achieve MAP similar to the control GNS+V group. Body weights did not differ among the groups upon entry into the protocol and increased similarly among the groups. Non-fasting blood glucose was elevated in all groups in both male and female rats. Mean arterial pressure (MAP) was 108±2 mmHg in GNS+V but was elevated in the FHS+V male rats, 118±2 mmHg ( P<0.01). FHS+L and FHS+E displayed MAP similar GNS+V rats: 104±2 and 106±2 mmHg, respectively. GFR assessed by transdermal FITC-sinistrin elimination was similar across all groups: 0.85±0.04 (GNS+V), 0.86±0.08 (FHS+V), 0.94±0.10 (FHS+L), 1.13±0.12 ml/min/100 g bw (FHS+E). Female rats did not display elevated MAP: 108±1 mmHg (FHS+V) vs 105±2 mmHg (GNS+V). Losartan and enalapril did not change MAP, but GFR was higher in female FHS+L rats, 1.14± 0.05, vs GNS+V 0.75±0.06 ( P < 0.05). Thus, male but not female fructose-fed rats on high salt diet display significantly higher blood pressure. Short-term fructose high salt feeding did not change GFR in either male or female rats. RAS inhibition did not impact GFR in male rats, but losartan increased GFR in female rats on high fructose plus high salt diet compared with glucose-fed female rats on normal salt diet.

R01 HL163844.

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.
Chronic UCN2 Administration Alters Muscle Mass, Exercise Metabolism, and Exercise Capacity in Lean Mice
Authors: Janzen Natalie , Wade Mark , Bauer Steven , Ryan Andrew , Brozinick Joseph
Published: May 2024

Urocortin 2 (UCN2) is a member of the corticotropin-releasing hormone (CRH) family and an agonist of the G protein-coupled receptor CRH receptor type 2 (CRHR2), which is highly expressed in skeletal muscle but absent from liver in both rodents and humans. UCN2 overexpression or chronic administration increases muscle mass in both lean and diet-induced obese (DIO) mice and is also believed to increase peripheral insulin sensitivity, reminiscent of the effect of acute exercise. However, how these effects of UCN2 may impact muscle function and exercise capacity remain incompletely understood. We hypothesized that treatment with a long term UCN2 treatment would increase lean and muscle mass and improve aerobic exercise capacity in lean, healthy mice. Lean 10-week-old male C57Bl/6J mice completed treadmill acclimatization and an incremental running test to exhaustion to determine maximal running distance and peak oxygen consumption (VO2). Mice were assigned to sedentary or maximal running groups and were treated with UCN2 for 18 days. After the final dose, body composition was assessed by qNMR. Vehicle- and UCN2-treated mice assigned to the maximal running group completed a second maximal test, and immediately upon completion of exercise, blood glucose was measured, and tissues were collected. Blood glucose and tissues were collected from sedentary vehicle- and UCN2-treated mice in the fed state. UCN2 treatment increased food intake, qNMR lean mass, and individual muscle weights. UCN2-treated mice had reduced maximal running distance, peak VO2, and blood glucose in response to exercise compared to vehicle mice. In addition, UCN2-treated mice had reduced hepatic glycogen in both the sedentary and post maximal exercise states. Gastrocnemius muscle from sedentary UCN2-treated mice had increased glycogen content and reduced phosphorylation of glycogen synthase. Following maximal exercise, UCN2-treated mice had higher gastrocnemius glycogen compared to vehicle mice. This indicated similar total glycogen utilization between treatment groups in response to maximal exercise, despite UCN2-treated mice performing less work. Follow-up studies in sedentary mice demonstrated UCN2 dosing increased phosphorylation of proteins involved in insulin-dependent and -independent glucose uptake in gastrocnemius muscle. These findings indicate that UCN2 affects whole-body and muscle substrate utilization and glucose regulation and signaling which results in increased muscle mass and altered exercise capacity. However, the unpredictability of the effects of UCN2 agonism on these parameters requires much further study.

This research was funded by Eli Lilly and Company.

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.
Effects of Perceived Social Stress on Cerebrovascular Hemodynamics in Young and Middle-Aged Adults
Authors: M Frescoln Abby , S Reed Krista , Gidley John , Churchill Sydney , D Meyer Jacob , K Lefferts Wesley
Published: May 2024

Depression is associated with altered cerebrovascular hemodynamics, including lower cerebral blood flow, higher cerebral pulsatility, and greater arterial stiffness. There is evidence that perceived stress may contribute to depressive symptomology, but it is unknown if stress may directly impact cerebrovascular hemodynamics. The purpose of this investigation was to examine associations among middle cerebral artery (MCA) hemodynamics, arterial stiffness, and perceived stress in young and middle-aged adults. It was hypothesized that individuals with higher reported social stress would have lower MCA mean velocity and higher MCA pulsatility and arterial stiffness. Methods: 168 adults (range 18-64 years; 40 ± 16 years; BMI 26.6 ± 4.6 kg/m2; n=88 females) underwent resting cerebrovascular measures and completed the self-reported perceived stress scale (PSS-10). Brachial blood pressure and carotid pulse pressure were assessed via oscillometric cuff and tonometry, respectively. Arterial stiffness was assessed as carotid-femoral pulse wave velocity (cfPWV) via tonometry and MCA mean velocity and pulsatility index were assessed via Transcranial Doppler. Results: The sample contained 4 adults with high (PSS score ≥27; mean, 28 ± 1), 38 adults with moderate (PSS score 14-26; mean, 17 ± 2), and 126 adults with low stress (PSS score <13; mean, 8 ± 3). Self-reported perceived stress was not significantly linearly associated with MCA mean velocity (r=-0.10), MCA Pulsatility Index (r=-0.08), or arterial stiffness (r=0.05). A secondary analysis comparing adults with moderate/high stress (n=42) to adults with low stress (n=126) revealed a significantly lower MCA mean velocity among moderate/high stress adults (p<0.05), however this difference was attenuated and no longer statistically significant after covarying for age. Conclusions: This data suggests that perceived stress 1) is not associated with altered cerebrovascular hemodynamics or arterial stiffness in our sample of generally healthy young and middle-aged adults, and 2) may not play a major role in altering cerebrovascular hemodynamics in the context of stress-related disorders (e.g., depression), however future research is required to directly test this hypothesis.

Iowa State University College of Human Sciences Faculty Seed Grant.

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.
Vascular responses during handgrip exercise in healthy postmenopausal females and older males
Authors: Oubouchou Katia , Debray Amélie , Ravanelli Nicholas , Saboune Jinan , W. Usselman Charlotte , A. Romero Steven , Gagnon Daniel
Published: May 2024

Introduction: Aerobic exercise interventions improve peripheral endothelial function in healthy older males. However, this effect is not always observed in healthy postmenopausal females and possible mechanisms underlying this sex-related difference remain unknown. Greater vascular shear stress during acute exercise is a key stimulus mediating longer-term improvements in vascular function. It remains unknown if postmenopausal females display a reduced endothelial sensitivity to exercise-induced shear stress relative to males of similar age. Objective and hypothesis: The objective of this study is to test the hypothesis that healthy postmenopausal females exhibit a lower endothelial sensitivity to exercise-induced shear stress relative to males. Methods: Fourteen healthy postmenopausal females (67 ± 8 years) not under hormone replacement therapy and 9 males of similar age (65 ± 7 years) performed handgrip exercise for 4 minutes at 20%, 40%, 60%, and 80% of their maximal voluntary contraction. Each exercise bout was separated by a 10-min recovery period. Brachial artery diameter and blood velocity were continuously measured using high-resolution ultrasound and analyzed using edge-detection software. Endothelial sensitivity to shear rate was quantified as the slope of the linear regression between brachial artery dilation (% change from baseline) and shear stress and compared between groups with an independent t-test. Workload, vascular conductance, diameter dilation, and shear stress were analyzed with mixed-effects models. Results: Males exercised at greater workloads relative to females across all exercise bouts (M: 17 ± 11 vs. F: 9 ± 5 kg, p<0.01). Forearm vascular conductance was greater in males throughout each exercise intensity (M: 2.23 ± 1.70 vs. F: 1.03 ± 0.51 ml/min/mmHg, p=0.02). Despite these differences, arterial dilation (M: 5.32 ± 5.55 vs. F: 5.20 ± 4.80%, p=0.96) and shear stress (M: 142 ± 80 vs. F: 171 ± 86 s−1, p=0.27) did not differ between groups across exercise intensities. Endothelial sensitivity to exercise-induced shear stress did not differ between males (0.02 ± 0.05%/s−1) and females (0.03 ± 0.01%/s−1, p=0.67). Conclusion: These data suggest that a reduced endothelial sensitivity to exercise-induced shear stress may not explain why aerobic exercise interventions do not consistently improve peripheral endothelial function in healthy postmenopausal females.

Montreal Heart Institute Foundation.

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.