bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of GPR19 drives obesity-related cardiac dysfunction in mice
Authors: Mushala Bellina , Xie Bingxian , McMahon Brenda , Thapa Dharendra , Jurczak Michael , Scott Iain
Published: May 2023

Background: Obesity is the second leading cause of preventable death in the United States and serves as a fundamental risk factor for cardiovascular disease. Dysregulated energy metabolism in hearts from obese subjects constrains cardiac contractile function under conditions of increased workload. G protein-coupled receptor (GPCR) signaling cascades play a key role in cardiovascular homeostasis, and are potential therapeutic targets to alleviate obesity-induced cardiac dysfunction. GPR19 is a poorly characterized class A orphan GPCR that is differentially expressed in several peripheral tissues, including robust expression in the heart. Recent reports from our group implicate GPR19 in a novel signaling pathway regulating mitochondrial energy metabolism in cardiac cells. However, evidence of its pathophysiological relevance in systemic or tissue-specific homeostasis has yet to be elucidated. Hypothesis: We hypothesize that GPR19 signaling mediates nutrient signaling and cardiac energy metabolism to preserve myocardial contractile function in diet-induced obesity. Methods: We used novel whole-body GPR19 knockout mice and subjected them to metabolic cage, echocardiography, and isolated perfused working heart analysis. This preliminary characterization was designed to understand the systemic effects of GPR19 depletion on cardiac and whole-body physiology under low-fat and high-fat fed conditions. Results: We report that GPR19 KO mice exhibit sex-dependent changes in both body and heart weight, increased energy expenditure, decreased physical activity, and markers of altered cardiac hemodynamics and energy metabolism. Conclusion: These findings define a new role for the GPR19 signaling pathway in the regulation of cardiac metabolic homeostasis, and thus highlight it as a potential target for therapeutic interventions in obesity-induced cardiovascular dysfunction.

The project described was supported by NIGMS T32GM133332 and NHLBI R01HL147861.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Emodin protects lipopolysaccharide-induced myocardial injury and mitochondrial dysfunction via PI3K/AKT signaling pathway based on Network Pharmacology
Authors: Liu Yanru , Liu Hanqiong , Sun Wenwen , Li Tao , Lin Bohan , Liu Wei , Zhang Hao , Shi Liang
Published: May 2023

Sepsis combined with myocardial injury is an important cause of septic shock and multiple organ failure. Cardiac dysfunction is a significant manifestation of sepsis and it is associated with the prognosis of the disease. It is assumed that damage to myocardial mitochondrial function is one of the main causes of cardiac dysfunction in septic patients, and the repair of myocardial mitochondrial function may alleviate cardiac dysfunction in septic patients. Emodin has been discovered to serve a variety of pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, and anti-apoptotic properties. In this study, we investigated the potential protective effect of Emodin on sepsis and revealed the underlying mechanisms using a network pharmacology approach coupled with experimental validation. The model of myocardial injury induced by LPS was established and divided into three groups: the control group, the lipopolysaccharide (LPS) group, and the LPS+Emodin group. The apoptosis rate, reactive oxygen species (ROS), mitochondrial permeability transition pore(MPTP), and mitochondrial membrane potential (MMP) were determined in LPS-induced sepsis Cardiacmyocytes treated with different concentrations of Emodin. In addition, the degree of myocardial mitochondrial damage was evaluated by electron microscopy. Signal pathway-related proteins were determined by Western blotting in vitro. And then, network pharmacology screening revealed TP53, CASP3, ILB, MYC, TNF, PTGS2, and PPARG as the critical overlapping targets in a PPI network, and GO and KEGG analyses revealed the top 10 enriched biological processes and signaling pathways associated with the therapeutic effects of emodin on sepsis. The results show the PI3K-AKT pathway is mainly involved in the emodin-sepsis myocardial injury network. Meanwhile, Emodin has been demonstrated to protect the myocardium from LPS-induced myocardial injury in vitro, and moderate doses of Emodin showed the most prominent effect. Emodin alleviates mitochondrial damage by reducing apoptosis and inhibiting oxidative stress and ameliorates protecting LPS-induced myocardial injury and mitochondrial dysfunction through the PI3K-AKT pathway. This provides a feasible strategy for preventing and treating myocardial injury and mitochondrial dysfunction in sepsis.

This study was supported by the Science and Technology Bureau of Zhengjiang (Grant No.SH2022068 and SH2022042).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A novel mouse model for an inducible gene-modification in the renal thick ascending limb
Authors: Bourqui Laurent , Winter Denise V. , Odermatt Alex , Loffing-Cueni Dominique , Loffing Johannes
Published: May 2023

The thick ascending limb (TAL) is critical for the renal control of fluid and ion homeostasis. The function of the TAL depends on the activity of the bumetanide-sensitive Na-K-2Cl co-transporter NKCC2, which is highly abundant in the luminal membrane of TAL cells. The TAL function is regulated by various hormonal and non-hormonal factors. However, many of the underlying signal transduction pathways remain elusive. Here, we describe the characterization of a novel gene-modified mouse model for an inducible and specific Cre/Lox-mediated gene modification in the TAL. In these mice, a tamoxifen-dependent Cre (CreERT2) was inserted into the 3’ UTR of the Slc12a1 gene, which encodes NKCC2 (Slc12a1-CreERT2). Although this gene-modification strategy reduced endogenous NKCC2 expression at the mRNA and protein level, the lowered NKCC2 abundance was not associated with an altered urinary fluid and ion excretion. Likewise, the renal response to loop-diuretics or water restriction was similar in wildtype (wt) and in Slc12a1-CreERT2wt/tg mice. Immunohistochemistry on kidneys from Slc12a1-CreERT2 mice revealed strong Cre expression exclusively in TAL cells but not in any other nephron portion. Cross-breeding of these mice with the mT/mG reporter mouse line showed a very low recombination rate (0.22%) at baseline, but a complete recombination (100%) after repeated tamoxifen administration. The achieved recombination encompassed the entire TAL and included also the macula densa. Thus, the new Slc12a1-CreERT2wt/tg mouse line allows an inducible and very efficient gene-targeting in the TAL and hence promises to be a powerful tool to advance our understanding of the regulation of TAL function.

The research of Johannes Loffing is supported by the Swiss National Science Foundation (310030_143929/1) and the Swiss National Centre for Competence in Research “Kidney.CH”

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Constitutive Loss of Ptpn2 in Mice Causes Features of Anemia Including Iron Deficiency
Authors: Lei Hillmin , Shawki Ali , Spalinger Marianne , Canale Vinicius , Santos Alina , Chatterjee Pritha , Crawford Meli’sa , Manz Salomon , Scharl Michael , McCole Declan
Published: May 2023

Background: Anemia is the most frequent extraintestinal manifestation of inflammatory bowel disease (IBD) and is associated with the risk of Crohn’s disease. Anemia significantly impairs quality of life, increases hospitalization rates, and increases medical care costs of IBD patients. Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 ( PTPN2), in regulating iron homeostasis. Methods: Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) 3-week-old mice were analyzed for serum iron content, complete blood count parameters, and intestinal and extraintestinal non-heme iron. Protein and RNA from duodenal epithelial cells (DECs) were assayed by western blotting and qPCR. Localization of the brush border ferrous iron transporter, DMT1, and the ferrous iron absorption driver, NHE3, in duodenal tissue was determined by immunohistochemistry (IHC). Results: Ptpn2-KO mice had reduced i) serum iron ( p=0.0007; n=10); ii) serum iron carrier transferrin saturation ( p=0.0077; n=8); iii) hemoglobin ( p=0.0002; n=5); iv) hematocrit ( p=0.0023; n=5); v) intestinal non-heme iron: duodenum ( p=0.0128; n=10) and jejunum ( p=0.0006; n=8); and vi) extraintestinal tissue non-heme iron: liver ( p=0.0014; n=10), spleen ( p=0.04; n=10), kidney ( p=0.0004; n=7), and gastrocnemius muscle ( p=0.0436; n=9) vs. Ptpn2-WT and Het mice. This indicated that loss of Ptpn2 causes characteristics of anemia including decreased serum iron and tissue iron storage and impaired intestinal iron homeostasis. DEC gene expression of the intracellular iron storage molecule ferritin ( Fth1) was reduced ( p=0.048; n=4) while the basolateral cellular iron importer transferrin receptor 1 ( Tfrc1) was significantly increased ( p=0.0048; n=5) in Ptpn2-KO mice. Reduced FTH1 protein expression ( p=0.007; n=12) and increased TFRC1 protein expression ( p=0.0021; n=8) in DECs of Ptpn2-KO mice was confirmed by western blot, indicating cellular iron deficiency. DMT1 (n=6) and NHE3 (n=8) protein expression in DECs was unaltered, whereas IHC showed reduced apical membrane DMT1 and NHE3 in the duodenal epithelium of Ptpn2-KO mice (n=6), suggesting a possible mechanism of impaired intestinal non-heme iron uptake. Conclusions: Loss of Ptpn2 in mice causes features of anemia including iron deficiency associated with mislocalization of DMT1 and reduced apical membrane expression of NHE3. These findings identify a critical role for PTPN2 in regulating systemic iron homeostasis.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Establishing the reproducibility of mitochondrial capacity using near-infrared spectroscopy
Authors: Landers-Ramos Rian , Dietz Grace , Chartier Gregory , Knuth Nicolas
Published: May 2023

Near infrared spectroscopy (NIRS) has been used as a valid measure of skeletal muscle oxidative capacity. Some studies have indicated non-uniform measures of NIRS-derived measures of oxygen consumption within a specific muscle bed. Thus, determining standardization of protocols and reproducibility of NIRS-derived muscle oxidative capacity is critical to ensure trusted responses. OBJECTIVE: Establish the reproducibility of NIRS-derived skeletal muscle oxidative capacity within the medial gastrocnemius muscle. We hypothesized that assessments of mitochondrial capacity using NIRS would yield strong intra- and inter-day reproducibility. METHODOLOGY: Ten healthy adults (30 ± 11 years old) participated in two visits to the lab scheduled 2-7 days apart. For each visit, a NIRS device was placed on the belly of the medial gastrocnemius muscle of the subject’s dominant leg, and electrical stimulation pads were placed directly above and below the NIRS device. A pneumatic cuff capable of rapid inflation was placed on the same leg proximal to the tibiofemoral joint. Laying supine, electrical stimulation was applied for 30s followed immediately by 6 rapid arterial occlusions lasting 5s each with 5s recovery between occlusions. The protocol was repeated three times for a total of four tests, and a physiological calibration was performed to correct for changes in blood volume. Differences in oxygenated and deoxygenated hemoglobin (Hbdiff) were collected continuously using NIRS. Recovery rate constants (min-1) following electrical stimulation were derived from analyses of Hbdiff signals to estimate skeletal muscle oxidative capacity. Location of the device was marked, and the protocol was repeated 2-7 days later. Coefficient of variation (CV%) and intraclass correlation coefficients (ICC) was used to determine intra- and inter-day reproducibility of results. RESULTS: The average recovery rate constant for oxygen consumption was 2.09 ± 0.24 min-1 on Day 1 and 2.07 ± 0.25 min-1 on Day 2 (p=0.91). Day 1 CV and ICC for four repeated trials was 11.9% and 0.888, respectively. Day 2 CV and ICC was 12.1 % and 0.700, respectively. Inter-day CV was 10.1% and inter-day ICC was 0.881. CONCLUSIONS: The intra- and inter-day CV and ICC for mitochondrial capacity measures of the medial gastrocnemius indicated good reproducibility using NIRS. These data support the use of NIRS to reliably assess mitochondrial capacity in younger adults.

Supported by Towson University (TU) School of Emerging Technology, TU Summer Undergraduate Research Institute, and the APS John F. Perkins Research Enhancement Award

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Human physiology undergraduates display low baseline subjective and objective understanding of cardiovascular health disparities in LGBTQ+ populations
Authors: Moreira Jesse , Streed Carl , Silva Vanessa , Fetterman Jessica
Published: May 2023

Introduction: Cardiovascular disease (CVD) is known to disproportionately burden lesbian, gay, bisexual, transgender, queer, (LGBTQ+) communities. Few physiology classrooms, however, incorporate population-specific mechanisms of CVD, including Minority Stress and associated psychological/physiological sequelae, when discussing disease mechanisms. Hypothesis: We hypothesized that baseline student measures of understanding regarding LGBTQ+ CVD burden and mechanisms would be low. Methods: Students enrolled in an undergraduate senior-level Cardiovascular Pathophysiology course were surveyed using Qualtrics. Likert-scale questions assessed agreement with understanding of LGBTQIA2S+ health disparity presence and mechanism. Open-ended prompts evaluated objective ability to explain understanding of CVD mechanisms in LGBTQ+ populations. Results: Of the 45 survey respondents, 12 (27.3%) identified as cisgender men, 30 (68.2%) identified as cisgender women, and 2 (4.5%) identified as non-binary. Regarding self-reported race/ethnicity, 7 respondents (15.9%) identify as Latine/Hispanic, 23 (48.9%) as White, 21 (44.7%) as Asian, 2 (4.25%) as Middle Eastern, and 1 (2.15%) preferred not to disclose. For sexuality, 32 (66.67%) identified as Straight/Heterosexual, 5 (10%) as lesbian/gay, 6 (13%) as bisexual, 1 (2%) as asexual, and 4 (8%) as queer. The majority of respondents (66%) reported “no previous” or “minimal previous” exposure to CVD disparity in LGBTQIA2S+ populations. Median Likert score (1-5, 1 representing high disagreement and 5 high agreement) for agreement with understanding that LGBTQ+ individuals face specific health disparities was 5.0 (interquartile range (IQR) 25%-75%: 4-5), median Likert score for agreement with understanding the mechanisms of LGBTQ+ health disparities was 2.0 (IQR 25%-75%: 2-4), and median Likert score for student agreement with understanding of how to intervene in LGBTQ+ specific health disparities was 3.0 (IQR 25%-75%: 2-4). The majority of students (70%) responded “I do not know” to the open-response prompt regardingthe mechanisms associating CVD with psychosocial stress in LGBTQ+ populations. Conclusion: Undergraduate students are aware of the CVD burden in LGBTQ+ populations, but lack understanding of the mechanisms behind the increased CVD risk or how to intervene. Curricularreform addressing LGBTQ+ specific CVD mechanismsand the biology ofpsychosocial stress is neededto foster understanding and creatediversely-educated future clinicians and scientists.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of stocking density and antimicrobial inclusion on selected blood physiological variables of broilers grown to 3 kg
Authors: OLANREWAJU HAMMED , Magee Christopher , Collier Stephanie , Purswell Joseph
Published: May 2023

Lower stocking densities may play a significant role in minimizing difficulties such as necrotic enteritis when reducing or eliminating antimicrobials (antibiotic free; ABF) in poultry diets. As the demand for poultry and associated products increases, one of the major concerns centers on the question of whether stocking density elicits adaptive responses that are characteristic of physiological stress. This study investigated the effect of stocking density and antimicrobial inclusion on selected blood physiological variables of broilers grown to 3 kg at 42 days of age. A total of 888 1-d-old Ross x Ross 708 chicks were randomly distributed into 24 pens based on stocking density treatments assignment. The treatments consisted of 4 densities (29, 33, 39, and 42 kg/m2) with six replicates. Treatments were blocked within the room to account for any variations in room conditions. Treatment assignments were randomized within each block. Used bedding was obtained from commercial farms to simulate commercial conditions. Feed and water provided ad libitum. Birds were provided a three phase-feeding program (Starter: 0-14 d, Grower: 15-28 d, and Finisher: 29-42 d). Birds and feed were weighed on 1, 14, 28, and 42 d of age for growth performance. Blood samples were collected from the brachial wing vein of 3 birds per pen on d 21 and 42, which were then analyzed immediately for whole blood physiological variables. Blood plasma samples were analyzed for T3, T4, and corticosterone. Results show there was only effect of stocking density on pCO2, which was within physiological ranges for this species. In addition, blood glucose and plasma corticosterone concentrations were not affected by stocking density, suggesting an absence of physiological stress. In conclusion, stocking densities up to 42 kg/m2 with appropriate environmental management may be suitable for both poultry integrators and contract growers to enhance broilers production efficiency without compromising the welfare of broilers grown to 3 kg at 42 days of age.

USDA-ARS

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of home-based heat therapy on skeletal muscle blood flow during exercise in older adults
Authors: Cope Heidi , Richey Rauchelle , Ruiz Ysabella , Moore Amy , Olivencia-Yurvati Albert , Romero Steven
Published: May 2023

The arterial vasculature undergoes profound changes across the lifespan. This vascular aging manifests as structural (e.g., vascular rarefaction) and functional (e.g., endothelial dysfunction) maladaptations. These age-related maladaptations contribute to the hypo-perfusion of skeletal muscle during conditions that require an elevated blood supply and substrate delivery (e.g., exercise) by tipping the vasoactive balance in favor of vasoconstriction. Acute heat exposure increases body and tissue temperature, increases blood flow and shear stress throughout the arterial tree, and initiates a humoral response. Importantly, chronic exposure to these temperature-dependent stimuli may reverse age-related vascular dysfunction, thereby improving perfusion of active skeletal muscle (i.e., exercise hyperemia). However, the effect of chronic heat therapy on exercise hyperemia has never been explored. Therefore, the purpose of this pilot study was to test the hypothesis that home-based heat therapy would increase skeletal muscle blood flow in older adults performing plantar flexion exercise. Six older adults (5 women; 67 ± 4 years) performed graded (5, 9, and 14 kg) unilateral dynamic plantar flexion exercise before (pre) and after (post) 8 weeks of home-based heat therapy. Each session of heat therapy required participants to immerse their lower legs ~33 cm into a heated (~ 42°C) and circulated water bath 4 days per week, for 45 min per session. Dynamic plantar flexion exercise was performed using a duty cycle of 1 s contraction and 2 s relaxation. Superficial femoral artery blood velocity and diameter were measured via Duplex ultrasonography and used to calculate the change in blood flow measured from baseline to each stage of exercise. Vascular conductance was calculated as flow/pressure. The change in leg blood flow during exercise was increased following heat therapy ( P = 0.08 for main effect of time), an effect that was mediated by augmented vascular conductance (5 kg: pre, Δ143 ± 89 ml/min/mmHg vs post, Δ188 ± 89 ml/min/mmHg; 9 kg: pre, Δ225 ± 89 ml/min/mmHg vs post, Δ234 ± 89 ml/min/mmHg; 14 kg: pre, Δ264 ± 89 ml/min/mmHg vs post, Δ290 ± 89 ml/min/mmHg; P = 0.07). Our preliminary data suggest that home-based heat therapy increases skeletal muscle blood flow during exercise in older adults, and may serve as a pragmatic intervention to improve exercise and functional capacity in this population.

Supported by: American Heart Association TPA958179

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Comparing Extracorporeal Shockwave Therapy (ESWT) with Non ESWT Focused Care on Functional Outcomes in Calcific Tendinopathy of the Shoulder
Authors: Baloy Rodiel Kirby , Becquer Albert , Obnial Sara
Published: May 2023

Purpose: Apatite deposits within tendons are common conditions that may cause pain, loss of motion, and difficulty with function among active individuals. The modality known as Extracorporeal Shockwave Therapy (ESWT) has been utilized successfully in lithotripsy and has been investigated for its possible role in aiding calcification. This literature review aims to look at the state of evidence among previous randomized controlled trials examining the effects of ESWT on calcification within tendons in the upper extremities. Methodology: Extraction Systematic literature searches for randomized controlled trials between 2012-2022 were performed in the databases of PubMed, Academic Search Index, and Directory of Open access Journals, CINAHL, between November 3rd to November 11th, 2022. A total of four randomized controlled trials (full text available, PEDro score > 7, and conducted in the past 10 years) with a total of 238 subjects met methodological quality guidelines using the PEDro scale. Results: A total of 1,042 articles were screened, and 4 studies with a total population of n = 238 were included in the review. With trials using a variety of adjunct therapies and with differences in frequency, dosage, and treatment volume a meta-analysis was not conducted. There were statistically significant improvements reported in terms of pain and function in ESWT on calcific tendinopathy in 1 study (n= 42). On the other hand, non-ESWT clinically significant differences were found in the use of ESWT in 2 of the studies (n=144), and no effects in 0 of the studies (n= 0). A small majority of studies suggest that in the management of tendinopathies of the upper and lower limbs, ESWT has a clinically significant effect on pain and functional outcomes. Conclusion: A review of current randomized controlled trials presented limited evidence for the use of ESWT for upper and lower limb tendinopathies in humans. While the use of ESWT may improve pain and functional outcomes in humans, further studies on dosing, prescription, and risk of bias assessment are suggested.

Dr. Baloy has no relevant financial or nonfinancial relationships to disclose. Mr. Becquer has no relevant financial or nonfinancial relationships to disclose. Ms. Obnial has no relevant financial or nonfinancial relationships to disclose.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Intranasal delivery of kisspeptin-54 improved mood-related disorders in hemiparkinsonian rats
Authors: Gemici Aysegul , Derin Narin , Sinen Osman
Published: May 2023

This study was designed to investigate whether chronic intranasal administration of kisspeptin-54 ameliorates anxiogenic- and depressive-like behaviors in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. We also tested the hypothesis that intranasal delivery of kisspeptin-54 would prevent against dopaminergic neuron loss in hemiparkinsonian rats. Male adult Sprague Dawley rats (age, 12 weeks; weight, 280-300 g) received a unilateral injection of 6-OHDA or vehicle into the medial forebrain bundle. Vehicle or kisspeptin-54 treatments (0.1, 0.3, 1, and 3 nmol applied topically on the rhinarium) were performed for 7 consecutive days following 6-OHDA surgery. Seven days after the lesion surgery, the sucrose preference test (SPT) and elevated plus maze test (EPMT) were used to measure depression- and anxiety-like behaviors, respectively. Tyrosine hydroxylase immunoreactivity in substantia nigra and striatum was analyzed by immunohistochemistry. Outcomes were analyzed between the experimental groups using ANOVA followed by Tukey posthoc test. As compared with sham-operated control rats (entry: 12 ± 2.3, time: 61.9 ± 1.6 s, n=10), 6-OHDA-lesioned rats made fewer open arm entries (6.1 ± 1, p<0.05, n=10) and spent less time (27.1 ± 3.9 s, p<0.05, n=10) on the open arms of EPM, inducing an anxiety-like behavior. In contrast, 6-OHDA-induced changes were found to be significantly (entry: 7.2-10.1 ± 2-1.7, time: 26.6-58.8 ± 2.5-3.1 s, p<0.05, n=10) improved in rats that received the chronic treatment of central kisspeptin-54 (dose-dependently). In the SPT, 6-OHDA-lesioned rats showed a lower (56.3 ± 3.5%, p<0.05, n=10) sucrose preference (considered an index of depression) in comparison to controls (80.7 ± 1.8%, n=10), and this decrease was dose-dependently restored to control levels by chronic kisspeptin-54 treatment (70.1-80.2 ± 2.8-2.7%, p<0.05, n=10). We also found that central kisspeptin-54 treatment significantly (p<0.05, n=5) attenuated the 6-OHDA-induced loss of dopaminergic nigrostriatal neurons. These data suggest that intranasal treatment of kisspeptin-54 improves 6-OHDA-induced anxiogenic- and depressive-like behaviors. Further, central kisspeptin-54 appears to be a promising therapeutic candidate for the treatment of mood-related disorders in Parkinson’s disease patients.

The present study was supported by The Research Foundation of Akdeniz University (project number: TSA-2022-5909)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Leptin signaling in the dorsomedial hypothalamus couples metabolism and breathing in obesity
Authors: Ramos Amorim Mateus , Wang Xin , Aung O , Bevans-Fonti Shannon , Anokye-Danso Frederick , Escobar Joan , Freire Carla , Pho Huy , Dergacheva Olga , Branco Luiz , Mendelowitz David , Polotsky Vsevolod
Published: May 2023

Individuals with obesity hypoventilation syndrome (OHS) are unable to increase ventilation to match increased CO2 production (VCO2). Obstructive sleep apnea (OSA), defined by the closure of the upper airway during sleep, is present in 90% of OHS patients. Leptin, an adipocyte-produced hormone, acts in leptin receptor (LEPRb) positive neurons and was implicated in the pathophysiology of OSA and OHS. Diet-induced obese (DIO) C57BL/6J mice shows features of OHS and OSA. Leptin-mediated neural pathways may link metabolism and breathing in obesity. We hypothesized that LEPRb-positive neurons in the dorsomedial hypothalamus (DMH) are necessary and sufficient to match control of breathing to VCO2 and that the stimulation of these neurons relieves OHS in DIO mice. We examined our hypothesis using in vivo and in vitro studies. We expressed designer receptors exclusively activated by designer drugs (DREADDs) in DMH of DIO Leprb-Cre mice and measured breathing during sleep, the hypercapnic ventilatory response (HCVR), VCO2, and O2 consumption (VO2). Activation of LEPRb-positive DMH neurons increased inspiratory flow and minute ventilation during REM sleep, without affecting sleep architecture. The effect was pronounced during inspiratory flow limitation, suggesting that upper airway obstruction during REM sleep was relieved. Activation of these neurons increased the HCVR and this response was blunted by a serotonin receptor antagonist, methysergide. Activation of these neurons augmented VCO2, VO2, and VE/VCO2, suggesting that breathing was stimulated out of proportion to increases in metabolism. In vitro experiments revealed that LEPRb-positive DMH neurons project to 5-HT neurons in the dorsal raphe (DR) and that optogenetic stimulation of these neurons evoked excitatory postsynaptic currents in 5-HT neurons of the DR. Administration of retrograde Cre-dependent AAV harboring caspase to the DR in Leprb-Cre mice deleted LEPRb-positive DMH neurons and abolished respiratory and metabolic effects of chemogenetic stimulation. Apoptosis of LEPRb-positive DMH neurons projecting to the DR also prevented the increase in ventilation during REM sleep induced by intranasal leptin. Leptin increases the HCVR, improves upper airway patency during sleep, and increases VCO2 acting on LEPRb-positive DMH neurons projecting to the DR. We conclude that LEPRb-positive DMH neurons projecting to the DR couple metabolism and breathing in obesity.

NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (#915167).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Efficacy Assessment and Mechanism Exploration of Multiple Functional Peptide on Restenosis Prevention
Authors: Chu Yi-hsuan , Wu Chieh-Hsi , Cheng Tsai-Mu
Published: May 2023

Restenosis is a common complication after balloon angioplasty, and the major mechanism is associated with abnormal proliferation and migration of vascular smooth muscle cells. To date, most of the clinically used vascular stent drugs are possessed of non-selective cytotoxic effects, which seriously affect the re-endothelialization of vascular endothelial cells, and increase the chances to form thrombosis and neointimal hyperplasia.Different haptoglobin (Hp) phenotypes have been clinically confirmed to be related to the incidence of restenosis. In our preliminary studies, Hp subunits also showed a variety of potential activities to inhibit restenosis. Therefore, the aim of this study is to explore if multiple functional peptide (MFP) of Hp subunits can be the potential protein drugs for preventing restenosis.The efficacy of MFP on resteneosis was evaluated by in vivo and in vitro studies. In the i n vivo study, male Sprague Dawley (SD) rats were subjected to tail vein injection of MFP twice a week right after the balloon angioplasty on common carotid artery. Two weeks after the angioplasty, the injured arteries were harvested for pathological assessment on neointimal formation by H&E staining.In the in vitro stduy, both endothelial cells (HUVEC) and smooth muscle cells (A10) were treated with various concentrations of MFP to evaluate their effects on cellular proliferation and migration. The antioxidant effects of MFP on malondialdehyde (MDA) formation and superoxide dismutase (SOD) activities were also assayed on macrophage cells.Our results demonstrated that in vivo administration of MFP can significantly suppress the neointimal formation induced by angioplasty. The positive regulatory effects of MFP on cellular proliferaiton and migration of HUVEC and negative effects on A10 may be the key molecular mechainsms of MFP on suppressing the neointimal formation found in the in vivo study. The antioxidant effects of MFP may also contribute to diminish the neointimal formation. The outcomes of this study will help to understand the feasibility, efficacy and safety of MFP as potential protein drug candidates for preventing vascular restenosis.

National Science and Technology Council

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
CKD patients have augmented beat-to-beat BP variability that is not improved with 12 weeks of cycling exercise
Authors: Sabino-Carvalho Jeann , Jeong Jinhee , Sprick Justin , Nardone Massimo , DaCosta Dana , Park Jeanie
Published: May 2023

Increased blood pressure (BP) variability is a powerful predictor of cardiovascular events and end-organ damage and is associated with sympathetic overactivity. Given the heightened cardiovascular (CV) risk in patients with chronic kidney disease (CKD), we hypothesized that patients with CKD would exhibit augmented resting beat-to-beat BP variability. Additionally, since aerobic exercise training exerts CV protective effects and has been shown to reduce resting sympathetic activity, we hypothesized that twelve weeks of aerobic exercise training would improve resting beat-to-beat BP variability in patients with CKD. In 25 sedentary patients with CKD stages III-IV [19 male/6 female, age: 62 ± 10 yr, 23 Black/2 White, systolic/diastolic BP: 130 ± 12/73 ± 9 mmHg, BMI: 31 ±7 kg/m2] and 15 controls [11 male/4 female, age: 56 ± 11 yr, 13 Black/2 White, systolic/diastolic BP: 129 ± 12/83 ± 8 mmHg, BMI: 29 ± 3 kg/m2], resting beat-to-beat blood pressure (finger photoplethysmography) was continuously measured for 5–10 min. Next, a subset of patients with CKD (n = 13) underwent 12 weeks of aerobic cycling exercise (spinning at 85% of maximal heart rate reserve). Exercise training was performed 45 minutes/session 3 days/week. All measurements were performed at baseline (n=40) and following the 12-week intervention (n=13). We calculated the standard deviation (SD), the coefficient of variation [CV (SD/mean)×100], and the average real variability (AVR) as indices of BP variability. Compared with controls, patients with CKD had significantly increased BP variability. The systolic SD BP (6.0 ± 2.1 vs. 3.9 ± 1.8 mmHg, P = 0.002) and the mean SD BP (3.9 ± 1 vs. 2.8 ± 1 mmHg, P = 0.006) were increased in CKD vs. Controls, but there were no differences in diastolic SD BP between groups (3.3 ± 1 vs. 2.6 ± 1 mmHg, P = 0.065). Similar results were found using AVR (Systolic AVR 2.0 ± 0.5 vs. 1.1 ± 0.5 mmHg, P > 0.001 and, Mean AVR, 1.3 ± 0.5 vs. 1.0 ± 0.3 mmHg, P = 0.010 for patients with CKD and controls respectively). Contrary to our hypothesis, we observed no significant change in resting beat-to-beat BP variability after 12 weeks of exercise in patients with CKD (SD SBP 6.3 ± 2.1 vs. 5.7 ± 2.0 mmHg, P = 0.893 and, AVR 1.9 ± 0.5 vs. 1.9 ± 0.6 mmHg, P = 0.970). In summary, our data demonstrate that patients with CKD have augmented beat-to-beat BP variability, and 12 weeks of cycling exercise did not reduce resting beat-to-beat BP variability in CKD patients.

This work was supported by National Institutes of Health Grants R01HL135183 and R61AT010457 (J.P).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
FBLN2 Abates Epigenetic-mediated Salt-sensitive Hypertension Through Regulation of NCC Trafficking
Authors: Han Xiaobin , Han Xiaobin , Chen Kai , Sun Zhongjie
Published: May 2023

Epigenetics play a role in the development of hypertension. However, the precise mechanisms of how histone modification in renal tubule cells regulates blood pressure is largely undiscovered. In this study, we investigated the role of renal Kdm6a in salt-sensitive hypertension using a kidney tubular cell-specific Kdm6a gene knockout (Kdm6a cKO) mouse model. First, we demonstrated that knockout of Kdm6a in the renal tubular cells resulted in an increase of H3K27me3 associated with the development of hypertension in both male and female Kdm6a cKO mice. To explore the mechanism of H3K27me3-mediated hypertension, we performed a ChIP seq to identify the target genes of H3K27me3 in the renal tubular cells. Data showed that H3K27me3 regulated several physiological pathways in the renal tubular cells, including sodium transport in proximal convoluted tubule (PCT), and blood pressure regulation in distal convoluted tubule (DCT). Indeed, we found that the expressions of NCC, NKCC2, and AQP2 were upregulated in kidneys of Kdm6a cKO mice. Furthermore, ChIP seq data reveals that FBLN2, an extracellular matrix protein, appears to be a target of H3K27me3, which was downregulated in the kidney of Kdm6a cKO mice determined by real-time PCR, Western, and IHC. Notably, we demonstrated that FBLN2 abated high salt-induced hypertension through downregulation of NCC, NKCC2, and AQP2 in the tubular cells of Kdm6a cKO mice. Interestingly, pre-treatment of FBLN2 prevented salt-sensitive hypertension in these mice. Additionally, we have provided evidence that FBLN2 may regulate blood pressure through mediating the NCC cell membrane trafficking. Using a super high-resolution microscopy, we demonstrated that FBLN2 reduced levels of cell surface NCC in DCT cells cultured in hypotonic medium. Here, we have first demonstrated that FBLN2 may be a target gene of H3K27me3 in epigenetic-mediated hypertension. FBLN2 treatment may prevent and treat salt-sensitive hypertension.

NIH

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Cholesterol, not fat, is critical in atherogenesis induced by intermittent hypoxia and hypercapnia
Authors: Xue Jin , Poulsen Orit , Meadows Jason , Zhou Dan , Haddad Gabriel
Published: May 2023

Obstructive sleep apnea (OSA) is a prevalent sleep disorder characterized by intermittent hypoxia and hypercapnia (IHC) and is known to increase risk for atherosclerosis. Most of OSA patients are obese. However, the particular role of high fat and high cholesterol in inducing or promoting atherosclerosis under IHC remains obscure. To dissect the mechanisms involved, we examined atherosclerotic formation in the Aorta, Aortic arch and Pulmonary artery (PA) in pro-atherogenesis mouse model, the apolipoprotein E ( ApoE) deficient mice, after IHC exposure on either high fat diet (HF, 60% fat by Kcal and 0.003% cholesterol by weight) or high fat high cholesterol diet (HFHC, 42% fat by Kcal and 1.3% cholesterol by weight), and compared them to room air (RA) control groups fed with HF, HFHC or regular chow (RC, 10% fat by Kcal and 0.003% cholesterol by weight). Our data revealed that HFHC-treated mice had significantly more atherosclerotic lesions than those fed with RC in room air (e.g. Aorta, RA-HFHC 8.1±0.76% vs RA-RC 1.0±0.27%, p<0.01). 10-week IHC treatment further accelerated atherogenesis in Aorta, Aortic arch and PA as compared to RA controls in the presence of HFHC (Aorta, IHC-HFHC 13.8±0.96% vs RA-HFHC 8.1±0.76%, p<0.01; Aortic arch, IHC-HFHC 28.5±1.88% vs RA-HFHC 16.6±2.00%, p<0.01; PA, IHC-HFHC 28.9±2.81% vs RA-HFHC 12.2±1.51%, p<0.01). Intriguingly, HF diet alone didn’t cause significant difference in terms of atherosclerotic lesions among RA-RC, Air-HF and IHC-HF groups (Aorta, IHC-HF 0.6±0.20% vs RA-HF 0.1±0.06% vs RA-RC 0.4±0.08%, p>0.01; Aortic arch, IHC-HF 2.0±0.73% vs RA-HF 0.4±0.20% vs RA-RC 1.0±0.26%, p>0.01; and PA, IHC-HF 1.4±0.33% vs RA-HF 0.2±0.20% vs RA-RC 0.0±0.04%, p>0.01), indicating that high fat alone is insufficient to induce atherosclerosis under both RA and IHC conditions. In conclusion, our data demonstrated that (1) high cholesterol, but not high fat, plays a critical role in the development of atherosclerosis; (2) impact of IHC on atherosclerosis depends on the presence of HFHC.

This study is supported by the National Institutes of Health grant 1R01HL157445-01A1.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Periodontitis accelerates the development of arterial hypertension in spontaneously hypertensive rats (SHR)
Authors: Buzinari Tereza , Castania Jaci , Salvador Sergio , Salgado Helio
Published: May 2023

Objectives: Arterial hypertension and the inflammatory process are pathophysiologically associated. Of note, it is well understood that periodontitis is an inflammatory morbidity, epidemiologically related to cardiovascular mortality, particularly with the risk of developing arterial hypertension. Considering that in Spontaneously Hypertensive Rats (SHR) the elevation of arterial pressure starts from the 7th week of age, this study aimed to evaluate whether periodontitis accelerates the onset of arterial hypertension, for instance, in 5-week-old SHR. Methods: Induction of periodontitis was started in 3-week-old SHR and maintained for 2 weeks through the ligation of the left first molar with a silk suture, followed by the Porphyromonas gingivalis (strain W83) administration, p.o., 3 times a week. The femoral artery of 5-week-old SHR was cannulated, and 24 hours later, with the animals awakened, the systolic (SAP), diastolic (DAP), and mean (MAP) arterial pressures were recorded. Results: 5-week-old control SHR (SHAM) did not have installed arterial hypertension, while SHR with periodontitis (PER) exhibited a higher arterial pressure when compared to the SHAM group (SAP PER: 150±4 vs. SAP SHAM: 124±3 mmHg, n=8, p≤0.001; DAP PER: 103±5 vs. DAP SHAM: 85±5 mmHg, n=8, p≤0.05; MAP PER: 119±4 vs. MAP SHAM 98±4 mmHg n=8, p ≤0.01). Conclusion: The differences observed in the pressure values between the groups studied demonstrate that periodontitis accelerates the development of hypertension in SHR.

Funding Sources: Fundação de Amparo à Pesquisa do Estados de São Paulo - FAPESP, Process 2021/08622-7 and 2020/06043-7. Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq, Process 306994/2021-6 and 423999/2021-4.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Sex based differences in muscle regeneration
Authors: Liu Siyu , Kostek Matthew , Omstead Kailey
Published: May 2023

Background: Normal skeletal muscle healing can be affected by various factors including biological sex. Males and females differ in the healing process such as the time course of the inflammation, recovery of muscle force, and period of regeneration. How exactly these processes differ is not well understood. Glycerol injections are a novel chemical model of skeletal muscle injury that mimic aspects of muscular dystrophy but currently there are no sex comparisons for this model. Therefore, the purpose of this study is to compare the difference in skeletal muscle healing between males and females, in a time course study, using this new method. Method: Male and female mice were split into two groups. Mouse gastrocnemius muscle was injected with glycerol (experimental) or saline (control) on day 0. Muscle physiology testing was performed 3 days (n=14) and 12 days (n=14) after injection, followed by hind-limb muscle collection and preservation for H&E, F480, necrosis, and eMyHC histological analysis. Result: Male groups had significantly higher muscle force production than the female groups (p<0.001). The improvement of muscle force production in the female group from 3 days to 12 days is significant (p<0.05), but the recovery of males did not reach statistical significance during this time period (p=0.659). There was greater pathology in the female group than the male group at 12 days after glycerol injection. Muscle regeneration occurred more at 12 days in females based on eMyHC analysis (p<0.05). Histological analysis is ongoing, but preliminary observations concur with the muscle physiology testing. Conclusion: The timeline of the muscle repair is different between the male and female groups. Muscle repair and regeneration are still ongoing at 12 days, which means interventions can be applied and studied during this time period. The difference in muscle regeneration between male and female groups is possibly due to hormone effects such as estrogen. Our laboratory is currently planning therapeutic trials based on levels of estrogen and exercise.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.