bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ataxia Telangiectasia-Mutated Kinase Deficiency Induces Cardiac Dysfunction with Increased Myocyte Apoptosis and Hypertrophy with Age
Authors: Dinnes Brooke , Foster Cerrone , Singh Krishna , Dalal Suman 
Published: May 2024

Background: Heart failure is the leading cause of death globally. The risk for heart disease increases exponentially with age. The incidence of heart disease is approximately 40% in humans that are 40-59 years old. Ataxia telangiectasia-mutated kinase (ATM), a cell cycle protein, controls growth and repair in response to double-stranded DNA damage. Mutations in the ATM gene lead to a multisystemic disease known as Ataxia Telangiectasia (A-T). These individuals exhibit signs of premature aging. A-T heterozygotes make up about 2% of the population and are more susceptible to ischemic heart disease and die 11 years earlier compared to non-carriers. Previous work has shown that ATM deficiency increases myocyte hypertrophy in 4-month-old (young) ATM heterozygous knockout (hKO) mice vs. age-matched wild-type (WT) mice. However, there was no difference in myocyte apoptosis or heart function between the two groups. Hypothesis: It is hypothesized that with age, ATM deficiency induces myocytes apoptosis and hypertrophy, and cardiac dysfunction. Methods: Heart function was measured in young and 14-month-old WT and hKO mice using echocardiography. Cross sections (5 μm) of heart were used to measure myocyte apoptosis and hypertrophy using terminal deoxynucleotidyl transferase nick end labeling (TUNEL) and rhodamine wheat germ agglutinin (WGA) staining, respectively. Results: Heart function, measured by fractional shortening (%FS) and ejection fraction (%EF), remained unchanged in young and 14-month-old WT mice. However, %FS and %EF were significantly lower in 14-month-old hKO mice vs. young hKO and age-matched WT mice. Myocyte apoptosis and cross-sectional area (hypertrophy) were significantly higher in 14-month-old hKO vs. age-matched WT mice. Conclusion: The data indicates that ATM deficiency induces cardiac dysfunction with increased myocyte apoptosis and hypertrophy with age. This research was supported by Department of Biological Sciences, Undergraduate Research Honors Program, Offce of Research and Sponsored Programs, Department of Biomedical Sciences, and Department of Health Sciences. 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.
Cervical lymphatic vessel dysfunction induced by amyloid-β and in the 5x-FAD mouse model of Alzheimer’s disease
Authors: Polk Felipe , Pires Paulo 
Published: May 2024

Alzheimer’s dementia is a multifactorial disease characterized by amyloid-β (Aβ) accumulation in the brain. Aβ clearance occurs partially via meningeal lymphatics into cervical lymph nodes through superficial cervical lymphatic vessels (sCLV), which relies on intrinsic contractions of sCLV. Previous studies showed increased Aβ build up in the brain following ablation of meningeal lymphatics; however, whether Aβ alters sCLV function remains unclear. We hypothesize that sCLV contractile function will be reduced by acute Aβ exposure and in the 5x-FAD mouse model of Alzheimer’s disease. Contractile function of freshly isolated sCLV was assessed using pressure myography. Acute Aβ exposure was achieved by intraluminal incubation of pressurized sCLV with Aβ(1-40) (5 μM) or vehicle for 15 minutes prior to the start of the experiment. Repeated end-diastolic (EDD) and end-systolic (ESD) measurements were used to calculate fractional pump flow (FPF), the product of contractile frequency (FREQ) measured as contractions per minute (Hz), and ejection fraction (EF) calculated as (EDD2-ESD2)/EDD2, at incremental intraluminal pressures ranging from 2 to 10 cmH2O. Statistical differences were determined by two-way ANOVA followed by Sidak correction for multiple comparisons. All data are means ± SEM. In sCLV isolated from 5 months-old males and females C57bl/6J mice, acute Aβ exposure significantly decreased FREQ (Vehicle vs Aβ, n=4 / n=7, p<0.01), without changes in EF (Vehicle vs Aβ, n=4 / n=7, p=0.115) or FPF (Vehicle vs Aβ, n=4 / n=7, p= 0.536). In pressurized sCLV isolated from 5x-FAD mice, when compared to wild-type littermates, we observed a significant reduction in FREQ (Wild-type vs 5x-FAD, n=4 / n=5, p<0.01). No differences were observed in EF (Wild-type vs 5x-FAD, n=4 / n=5, p=0.1224) or FPF (Wild-type vs 5x-FAD, n=4 / n=5, p=0.193). Together, these preliminary data suggest that acute exposure to Aβ(1-40) decreases FREQ of isolated sCLV, a similar effect observed in sCLV isolated from 5x-FAD mice, albeit not reaching statistical power for multiple comparison significance. Consequently, a decrease contractile frequency can contribute to impairments in lymphatic pumping, which to some extent, can be compensated by prolonged filling times, thus leading to increased ejection fraction. In conclusion, we predict that in vivo sCLV contractile function is maintained via compensatory increases in ejection fraction in conditions of exacerbated Aβ production and deposition. Funding: National Institutes of Health (R01 AG073230) and the Alzheimer’s Association (AARGD-21-850835). 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.
Dietary Fructose Regulates Kupffer Cell Metabolism and Plasticity
Authors: Lodge Mareca , Cottam Matthew , Richard Daniel , Adams Victoria , Liu Xiaojing , Kennedy Arion 
Published: May 2024

Over-consumption of fructose in humans have been linked to increased risk of Non-Alcoholic Fatty Liver Disease (NAFLD) and other metabolic diseases. Recent studies have suggested that fructose plays an important role in the development of liver inflammation, fibrosis, and immune cell activation during NAFLD. However, little work characterizes the direct impact of fructose on macrophage infiltration, phenotype, and function in the liver. Our studies demonstrate that chronic fructose exposure induces liver fibrosis and inflammation compared to control and glucose diets . Single cell RNA sequencing (scRNAseq) revealed fructose and glucose reduced Kupffer cells while increasing transitioning monocytes. However, fructose alone significantly increased expression of fibrosis and wound healing associated genes Mmp12, Il1rn, Rsad2, and Gpnmb in Kupffer cells. In vitro studies demonstrated that fructose treated immortalized Kupffer cells (IMKC) metabolize fructose through glycolysis and pentose phosphate pathway (PPP) by stable isotope tracing. Fructose treated IMKC cells showed reduced cell viability and increased Gpnmb, Tnfa, Mmp12, Il1rn, and Rsad2 gene expression. In addition, inhibition of the PPP further increased fructose induced Gpnmb, Mmp12, Il1rn, and Rsad2 in nonpolarized IMKCs. Taken together, fructose decreases cell viability while upregulating wound healing and fibrosis associated genes in Kupffer cells. This study was funded by the R21 DK128678 National Institute of Diabetes and Digestive and Kidney Diseases to AK. 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.
Sex-specific role for the clock protein PER1 in renal ET-1 regulation in salt-sensitive hypertension
Authors: Costello Hannah , Douma Lauren , Juffre Alexandria , Cheng Kit-Yan , Crislip G. Ryan , Zietara Adrian , Dissanayake Lashodya 
Published: May 2024

Global knockout (KO) of the clock protein PERIOD1 (PER1) in male, but not female, C57BL/6J mice displayed both blunted blood pressure and urinary endothelin-1 (ET-1) rhythms. More recently, we showed that Dahl salt-sensitive (SS) Per1 KO male rats had exacerbated SS hypertension, alongside increased renal injury, renal ET-1 gene ( Edn1) expression, and ET-1 peptide expression from kidneys collected during the rat’s inactive period (2 PM). Additionally, we see increased long non-coding RNA EDN1-AS, which has been suggested to modulate ET-1 production. However, it is unknown whether PER1 regulates rhythms of ET-1 in SS rats and whether PER1 regulates ET-1 in a sex-dependent way. The study objective was to test the hypothesis that PER1 negatively regulates renal EDN1-AS and Edn1 to modulate ET-1 in a sex- and time-dependent manner. To test this hypothesis, kidneys were collected during rat’s active period (2 AM) from male and female SS Per1 KO and SS control rats on a normal salt (0.4% NaCl) or 3 weeks high salt (4% NaCl) diet ( N=5-6). Renal ET-1 protein levels were measured by ELISA and semi- and quantitative PCR was performed to quantify the levels of EDN1-AS and Edn1. Renal ET-1 levels were significantly higher at 2 AM than our previously reported data at 2 PM in both SS Per1 KO and control male rats ( p<0.0001). Renal ET-1 levels were significantly increased in male SS Per1 KO rats following a high salt diet ( p=0.0362) but not in females ( p=0.9522). This was also reflected in the Edn1 mRNA levels (male, p=0.0005; female, p=0.0814). EDN1-AS levels were also increased in males ( p=0.0123) but not in females. Interestingly, significant sex differences were seen in EDN1-AS levels, where EDN1-AS levels were higher in males than females following both low and high salt diets, suggesting a potential novel sex-dependent mechanism for ET-1 regulation. Together, these data suggest sex-specific action of PER1 in the regulation of ET-1 in a model of salt-sensitive hypertension. Future work aims to investigate blood pressure and renal injury in female SS Per1 KO rats and whether this apparent negative regulation of ET-1 by PER1 contributes to the SS hypertensive and renal injury phenotype seen in male SS Per1 KO rats. This work was supported by the National Institutes of Health grants R35 HL135749 (to A.S.), R01 342 DK109570 (to M.G. and A.S.), and Department of Veteran Affairs grants I01 BX004024 (to A.S.). 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.
Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) acetylation status is an important regulator of adipose tissue thermogenic function
Authors: Chocron E. Sandra , Zhang David , Schell Joseph , Cruz Diego , Gius David , Gonzalez Porras Maria 
Published: May 2024

Brown adipose tissue (BAT) is a crucial regulator of metabolism specialized in dissipating energy in the form of heat. Cold stimulated BAT uses glucose and free fatty acids for thermogenesis, impacting adiposity, glucose control, and insulin sensitivity. Furthermore, the ability of white adipocytes in white adipose tissue (WAT) to transition into thermogenic or beige adipocytes in response to cold exposure or specific pharmacological activators makes them a promising target for developing therapies to address obesity and other metabolic diseases. Sirtuin 3 (SIRT3), an NAD+- dependent deacetylase found within the mitochondria, controls BAT thermogenesis. Loss of SIRT3 in mice results in compromised BAT lipid metabolism, as well as impaired thermoregulation and mitochondrial respiration in BAT, without affecting UCP1 expression and/or function. Acetyl-CoA Synthetase Short Chain Family Member-1 (ACSS1) is an established SIRT3 deacetylation target that synthetizes acetyl-CoA using acetate that is central for fatty acid oxidation (FAO) and mitochondrial metabolism. To understand the function of ACSS1 acetylation role in BAT and WAT during thermogenesis response, we generated a ubiquitous acetylation mimic knock-in mouse by mutating lysine 635 to glutamine (K635Q), previously shown to alter ACSS1 enzymatic activity, which represents a constitutive ACSS1-K635-Ac rendering a protein with altered functionality. Our studies showed that these mice are intolerant to stimulation with b3 adrenergic receptor agonist CL316243 and died within 24 hours. These mice are not able to maintain body temperature and glucose homeostasis and also displayed dysregulated levels of the major lipid synthesis and oxidation pathways in BAT and inguinal subcutaneous WAT (iWAT). Importantly, the CL316243 intolerant phenotype was not observed in Acss1 knock out mice. This data suggests ACSS1-Ac status is an important regulator of adipose cells/tissue thermogenic function, and therefore is a potential therapeutic target for metabolic diseases. These results open a new roadmap to improve metabolic health through post- translational control of ACSS1. Early Stage Investigator Award, Mays Cancer Center P30CA 054174. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
A novel antibody that neutralizes corticotropin-releasing factor attenuates the cardiovascular effects of chronic social defeat stress in mice
Authors: Scott Karen , Eikenberry Sophia , Johnson Dominique , Elsaafien Khalid , De Sa Jessica , Krumm Zachary , Golde Todd 
Published: May 2024

According to the World Health Organization, cardiovascular disease (CVD) continues to be the leading cause of death worldwide. While a myriad of genetic and environmental factors influence the development of CVD, there are several lines of evidence suggesting that psychological stress contributes to health disparities in CVD observed amongst different populations. Our lab seeks to understand the effects of psychosocial stress on cardiovascular health using a model of chronic social defeat stress (CSDS) in mice. In this paradigm, male C57BL/6 mice undergo brief daily defeat sessions and are housed in the same cage as the larger, more aggressive CD1 defeater mouse, separated by a polycarbonate divider that allows for continuous visual, auditory, and olfactory contact while preventing physical contact. We have previously demonstrated that this paradigm causes robust and persistent elevations in blood pressure, indices of chronic inflammation, elevations in plasma corticosterone and cardiac and adrenal hypertrophy. Social defeat also leads to robust activation of corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus (PVN). In the present studies, we investigate whether we can alleviate some of the adverse effects of CSDS through targeting the HPA axis using CTRND05, a novel anti-CRF antibody. Adult male C57BL/6 mice were assigned to either CSDS or control (paired) housing. Following 14 days of CSDS or control housing, mice were treated with one injection of CTRND05 (25 mg/kg, i.p.) or vehicle (IgG), followed by 14 more days of CSDS or control housing. A booster administration of CTRND05 (12.5 mg/kg, i.p.) was given 7 days after the initial dose. Adrenal weights were significantly reduced in pair housed mice treated with CTRND05 compared to pair housed mice treated with IgG, and there was a trend towards a reduction in adrenal weight of CSDS mice treated with CTRND05 in comparison with CSDS mice treated with IgG. There was also a trend for reduced basal corticosterone in CSDS mice treated with CTRND05. Importantly, while IgG treatment had no effect on the systolic blood pressure (SBP) of CSDS mice, treatment with CTRND05 significantly lowered the SBP of CSDS mice when compared with pre-treatment. These data suggest that targeting CRF may serve as a therapeutic tactic for treatment of stress-related hypertension. R35HL150750, R01HL136595. 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.
Left Ventricular Dilation Resulting from the Absence of Either Rgs2 or Rgs5 Is Associated with Increased Immune Cell Infiltration in the Myocardium
Authors: Dahlen Shelby , Nallapaneni Sanjana , Osei-Owusu Patrick 
Published: May 2024

Sustained sympathoexcitation is a hallmark of heart failure, with equally sustained activation of downstream signaling pathways involving Gs- and Gi/o-coupled β-adrenergic receptors (βAR) stimulating cAMP production and PKA activation. A critical mechanism controlling G protein-mediated βAR signaling is the activity of regulator of G protein signaling (RGS) proteins, including members of the B/R4 subfamily, which accelerate the termination of Gq/11 and Gi/o protein signaling. Previous studies by us and others reported that moderation of Gi/o activity separately by RGS2 and RGS5 of the R4 subfamily is key to maintaining normal ventricular rhythm. The loss of one or both R4 RGS proteins also results in left ventricular (LV) dilation and reduced ejection fraction. Here, we tested the hypothesis that the LV structural remodeling is due to the disruption of the coordinated activity of RGS2 and 5 resulting in sensitization of βAR signaling. To test this hypothesis, we challenged wild type (WT), Rgs2 KO ,Rgs5 KO, and Rgs2/5 double knockout (dbKO) adult male mice with sub-chronic infusion of isoproterenol (ISO, 30 mg/kg/day, 3 days) via a peritoneal osmotic minipump implantation. Rgs2 KO and Rgs5 KO mice showed increased LV chamber size at baseline, which was unchanged by ISO administration. In saline-treated animals, the loss of Rgs2 increased Rgs5 mRNA expression, while Rgs5 absence increased Rgs4 mRNA expression. ISO infusion induced concentric cardiac hypertrophy in WT mice, as evidenced by increased heart weight/tibia length (HW/TL) ratio and cardiomyocyte cross sectional area. While ISO infusion increased interstitial fibrosis in midventricular tissue and HW/TL ratio in dbKO mice, it did not affect cardiomyocyte cross sectional area or exacerbate LV dilation, despite increased expression of the cardiac fetal gene Nppa as well as the sarcomeric protein α-actinin and Ca2+/calmodulin-dependent kinase II (CaMKII). Cardiact tissue from saline-treated Rgs2 KO and Rgs5 KO mice had markedly increased CD45+ cells vs WT, while tissue from Rgs5 KO mice showed increased CD68+ cells, as revealed by immunohistochemistry. Taken together, these results indicate that ventricular remodeling seen in Rgs2 KO, Rgs5 KO, and Rgs2/5 dbKO mice is insensitive to sustained βAR stimulation but may be due to increased cardiac resident immune cell population. This work was supported by NIH R56 DK132859-01A1 and R01 HL139754, and Craig H. Neilsen Foundation Grant 382566 to Patrick Osei-Owusu. 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.
Time restricted feeding improves insulin resistance and reduces progressive proteinuria in young obese Dahl salt-sensitive rats prior to puberty
Authors: Mandal Sautan , Bhopatkar Anukool A. , Evans Lana , Johnson Alanis , Ekperikpe Ubong S. , Williams Jan M. 
Published: May 2024

Prepubertal obesity (PPO) is now associated with early signs of renal disease. An improper eating behavior is one of the leading causes of PPO. Time restricted feeding (TRF) has been shown to be beneficial in obese patients without reducing body weight. However, the effects of TRF on renal injury during PPO have not been investigated. Therefore, the current study examined whether TRF reduces renal injury in obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) rats before puberty. Four-week-old SS and SSLepRmutant rats were given either ad libitum access to food for 24 hrs (control) or 8 hrs during their active phase (TRF) for 4 weeks. Body weight and food intake were significantly higher in SSLepRmutant rats versus SS rats throughout the study, and TRF did not have an impact on both parameters. Fasting blood glucose levels were similar in all groups (≤120 mg/dL). Fasting plasma insulin levels were significantly higher in SSLepRmutant rats vs SS rats (5±1 vs. 1.0±0.1 ng/mL; p<0.05), and TRF reduced fasting plasma insulin by 70% in SSLepRmutant rats. Moreover, TRF markedly improved insulin resistance in SSLepRmutant rats. At the end of the study, we did not observe any differences in MAP (via carotid catheter) among the groups. Proteinuria was significantly higher in SSLepRmutant vs SS rats (361±32 vs. 17±4 mg/day; p<0.05), and TRF only reduced proteinuria in SSLepRmutant rats (144±19 mg/day; p<0.05). We observed a significant increase in GFR (via creatinine clearance) in SSLepRmutant rats compared to SS rats (0.71±0.08 vs. 0.39±0.07 mL/min/gkwt; p<0.05), and TRF normalized GFR in SSLepRmutant rats (0.37±0.07 mL/min/gkwt; p<0.05). Glomerular injury and renal fibrosis were markedly elevated in SSLepRmutant vs SS rats, and TRF improved these histological changes. Overall, these data suggest that TRF prevents the early progression of proteinuria by possibly reducing the insulin resistant effects on GFR during PPO. NIDDK (DK109133) and AG (AG057842). 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.
Pathological effects of electronic cigarette exposure in mouse pregnancies
Authors: Clark Evan , Stapley B , Mattingly J , Kirkham Maddie , Chang A , Reynolds Paul , Arroyo Juan 
Published: May 2024

Use of electronic Cigarettes (eCig) has increased worldwide in the last several years. Its use has been reported to be an effective smoking cessation tool and for being healthier than normal cigarette use. Although these reports exist, they lack supportive scientific evidence. Little is known about eCig effects during pregnancy. In the present study, we wanted to determine the effects of eCig exposure at two different important gestational points during mouse pregnancy in order to determine eCig exposure effects during pregnancy. C57/Bl6 mice were exposed to eCig via a nose-only delivery system (Scireq) for 4 days (from 14.5 gestational day (dGA) to 17.5 dGA) or for 6 days (from 12.5 dGA to 17.5 dGA). At the time of necropsy (18.5 dGA) placental and fetal weights were recorded. Maternal blood pressure was determined with a tail occlusion cuff (Kent Scientific) and proteinuria was detrained with the dip stick method. Markers for placental apoptosis were also determined. Treatment with eCig showed: 1) a significant decrease in placental weight and fetal weight (p<0.05) following 4 and 6 days of exposure, 2) higher systolic (p<0.02) and diastolic (p<0.02) blood pressure following 6 days of exposure, 3) increased proteinuria after 6 days of exposure, and 4) differential expression apoptosis markers in the placenta after 4 and 6 days of exposures. We conclude that detrimental effects of eCig coincides with the length of maternal exposure. We confirmed that 4 days of exposure resulted in metrics common to IUGR while 6 days of exposure more closely resembled PE/IUGR pathology. These results could be beneficial in understanding the long-term effects of eCig exposure and the development of placental diseases. This work was supported by the National Institutes of Health grant number 1R15HD108743. 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.