bluuebunny/crossref_metadata_2025 huggingface dataset:
Age‐Related Changes in Skeletal Muscle and Small Mesenteric Arterial Function in Spontaneously Hypertensive Rats
Authors: Jurrissen Thomas Jacob , Castorena‐Gonzalez Jorge A , Ramirez‐Perez Francisco I , Hill Michael A , Meininger Gerald A , Padilla Jaume , Martinez‐Lemus Luis A
Published: June 2021

Essential hypertension is a chronic idiopathic medical condition that is characterized by elevated arterial blood pressure and is associated with increased risk of cardiovascular disease. Endothelial dysfunction is associated with increased age and a casual factor for the development of hypertension. Therefore, we hypothesized that endothelial dysfunction would be exacerbated by age to a greater extent in spontaneously hypertensive rats (SHRs) compared to Wistar‐Kyoto rats (WKY) control rats. Vascular function was assessed using pressure myography in skeletal muscle and mesenteric resistance arteries isolated from SHR and WKY across three age groups: young (16–17 weeks, n = 4/group), aged (62–64 weeks, n = 4/group) and old (88–100 weeks, n = 5/group). Phenylephrine‐induced vasoconstriction responses in either of the resistance arteries were not significantly different between WKY and SHR at any of the age groups. Endothelial‐dependent vasodilation in mesenteric arteries was not significantly different between WKY and SHR across age groups either. However, endothelium‐dependent vasodilation in the skeletal muscle resistance arteries was significantly enhanced in the young SHR compared to WKY, but not in the aged or old rats. Moreover, endothelial‐independent vasodilation in mesenteric arteries was significantly enhanced in SHR compared to WKY across all age groups, while this difference was only observed in the skeletal muscle resistance arteries of the young rats. Contrary to our hypothesis, these data suggest that endothelial dysfunction is not exacerbated by age in the resistance arteries of SHR.

Support or Funding Information

Research support: National Institute of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Treatment of Hypertension with Stable Analogue of 14, 15‐Epoxyeicosatrienoic Acid (EET‐A) in Spontaneously Hypertensive Rats
Authors: Baranowska Iwona , Gawrys Olga , Walkowska Agnieszka , Husková Zuzana , Honetschlagerová Zuzana , Cervenka Ludek , Falck John , Kompanowska‐Jezierska Elzbieta
Published: June 2021

Introduction

Hypertension and concomitant complications, such as blood circulation disorders, stroke, heart attack or kidney failure, became one of the leading causes of death in the world. Recent reports indicate on epoxyeicosatrienoic acids (EETs) as significant factors in blood pressure regulation. These cytochrome P‐450 dependent metabolites of arachidonic acid, exhibit vasodilator and natriuretic activity. It has been shown that EETs facilitate the production of vasodilatory NO, protect the endothelium, exhibit antioxidant properties and might inhibit inflammation. All of the above‐mentioned features should contribute to the reduction of blood pressure and adverse effect of hypertension, hence we postulate the usefulness of EETs as novel drugs for the prevention and/or treatment of hypertension. In the present study the potential hypotensive efficiency of a stable analogue of 14,15‐EET: disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate, called EET‐A, in genetic model of hypertension (spontaneously hypertensive rat, SHR) was evaluated.

Methods

Male SHR (n = 6) in the established stage of hypertension (16 weeks) were treated for four weeks with EET‐A dissolved in drinking water (10 mg/kg/day); aged‐matched control group received water only (n = 6). Systolic blood pressure (SBP) was measured by telemetry technique every three days. Once a week observations in metabolic cages (food and water intake, feces, diuresis) were performed; urine and blood samples were collected for further analysis. Nitric oxide metabolites and vascular endothelial growth factor (VEGF) content in urine was measured with commercial ELISA kit.

Results

Preliminary results showed that EET‐A did not impact the blood pressure of adult SHR. We did not observe any changes in diuresis, water and food intake. Also sodium excretion did not change after EET‐A treatment, however, surprisingly, it significantly increased in the control group (EET‐A day 0: 0.5 ± 0.1 vs day 28: 0.5 ± 0.1, NS; control group day 0: 0.4 ± 0.2 vs day 28: 1.0 ± 0.1#* mmol/24h, *p<0.05 within the control group; # values on day 28th between groups, p<0.05). The excretion rates of NO metabolites (nitrates/nitrites; NOx) and VEGF‐A increased significantly in the EET‐A treated group (NOx day 0: 0.99 ± 0.18 vs day 28: 1.56 ± 0.13 μmol/24h, p<0.05; VEGF‐A day 0: 3.2 ± 0.7 vs day 28: 9.5 ± 2.0 ng/24h, p<0.05).

Analysis of the obtained data suggests that EET‐A in the applied dose does not lower blood pressure. Further studies are necessary to investigate if, despite the lack of blood pressure decrease, EET‐A improved kidney function.

Support or Funding Information

National Science Centre 2017/26/M/NZ5/00367

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Two‐Weeks of Remote Ischemic Preconditioning Alters Sympathovagal Balance
Authors: Gardner Richard N , Sabino‐Carvalho Jeann L , Vianna Lauro C , Lang James A
Published: June 2021

Remote ischemic preconditioning (RIPC), elicited by brief, intermittent periods of ischemia followed by reperfusion, has cardioprotective effects. Our lab recently found that repeated bouts of RIPC improves microvascular function; however, it is unclear whether autonomic function would also be affected. We hypothesize that heart rate variability (HRV) will be altered following two weeks of repeated RIPC. Eleven healthy adults (age = 22 ± 2 yrs, 6 males, 5 females, BMI = 23.1 ± 3.4) performed two weeks of RIPC over 3 four‐day periods, each separated by a one‐day break. Each RIPC session consisted of 4 repetitions of 5 minutes of arm blood flow occlusion interspersed by 5 minutes of reperfusion. Before and one day after two weeks of RIPC, resting heart rate was collected with lead II electrocardiogram (ECG) while the participant was comfortably lying in a semi‐recumbent position in a quiet, dimly lit thermoneutral environment. Power spectral density and symbolic dynamics were used to assess HRV from ~350 beat ECG segments. Two weeks of repeated RIPC decreased the percentage of 0V beat fragments (pre‐RIPC = 13.1 ± 6.5%, post‐RIPC = 6.9 ± 4.9%, P < 0.05) and increased the percentage of 2V beat fragments (pre‐RIPC = 42.9 ± 12.1%, post‐RIPC = 52.5 ± 10.0%, P < 0.01), while decreasing the LF/HF ratio (pre‐RIPC = 1.1 ± 0.6, post‐RIPC = 0.7 ± 0.3, P < 0.01). Thus, both the spectral and fractal analyses indicate that repeated RIPC shifts sympathovagal balance by increasing parasympathetic and decreasing sympathetic activity.

Support or Funding Information

Funded by the Iowa Space Grant Consortium

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endothelial cell‐mediated formation of high density lipoprotein‐like particles
Authors: Yang Hong , Zhang Ningya , Okoro Emmanuel U. , Hairston‐Paschall Jenaqua , Guo Zhongmao
Published: June 2021

Passage of plasma triglyceride‐rich lipoproteins (TRLs) and low‐density lipoproteins (LDLs) through the monolayer endothelium occurs in normal and atherosclerotic arteries. The current report studied the effect of transendothelial transport on the density distribution of TRL‐ and LDL‐associated cholesterol and apolipoproteins (apo). Our data indicated that the 3H‐cholesterol and 125I‐apoE in the TRLs and LDLs that were not incubated with the mouse aortic endothelial cell (MAEC) monolayer distributed primarily in the low density (LD) fractions (d: ≤1.063). In contrast, a substantial portion of the 3H‐cholesterol and 125I‐apoE that had passed through the MAEC monolayer were allotted into the high density (HD) (d: ≥1.063) fractions. ApoB protein was detectable only in the LD fractions before or after TRLs or LDLs were incubated with the MAEC monolayer. Inhibition of caveolae‐dependent endocytosis reduced the transendothelial transport of TRLs and LDLs and its associated apoE‐carrying HD particle formation. These suggest that TRLs and LDLs pass through the MAEC monolayer in the forms of apoB‐carrying LD particles and apoE‐carrying HD particles.

Support or Funding Information

NIH SC1HL101431

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Study of a New Working Memory Paradigm for Hypertensive Patients
Authors: Paradela Regina , Cabella Brenno , Nucci Mariana Penteado , Irigoyen Maria Claudia
Published: June 2021

Working memory (WM) has been extensively explored in the field of cognitive neuroscience, and several programs have been developed to train this ability in different clinical conditions. Among them, Cogmed stands out, since its effects have shown beneficial for many populations, but few studies have evaluated the effects of this training on brain function. In addition, none of these studies were with hypertensive patients who are known to have deficits in executive functions, including WM. Therefore, the aim of this study was to evaluate the neuronal activation of hypertensive patients during a WM task. A next step will be to re‐evaluate activation after training with Cogmed and compare it with pre‐training. The results described are related to the pilot study carried out to evaluate the feasibility and adequacy of the proposed protocol. The pilot study was composed by two stages: 1) stimulus programming in E‐prime software version 1.2; and 2) acquisition of structural and functional images on a 3.0 T magnetic resonance imaging device, followed by analysis of the activation of brain areas of interest. The paradigm was adapted from Brehmer et al., 2011 and consists of two active conditions with different levels of difficulty, Low (4 stimuli) and High (6 stimuli), and their respective controls. The sample consisted of 4 healthy young volunteers and 1 patient with hypertension, as an exploratory analysis for future study intervention. The activation map obtained corresponds to the group analysis of these volunteers and the term ‘activation’ refers to the positive BOLD contrast. In the group activation maps (n = 4 Z‐score> 2.3; p, <0.05), the most activated regions in Low were superior parietal lobe, precuneus, frontal lobe, medial frontal gyrus, pre‐central gyrus, cingulate gyrus, temporal lobe, fusiform gyrus and thalamus; in the High condition the most activated areas were superior parietal lobe, precuneus, insula, frontal lobe, medial frontal gyrus and thalamus; and in the comparison between the active conditions (High x Low), we observed higher activation in the High condition in the superior parietal lobe. These preliminary results showed that the paradigm is activating areas involved with WM processing and a statistically significant difference between the conditions tested. In this way, we considered the protocol adequate to evaluate the neuronal activation during a WM task in a larger group of volunteers (N = 40) with arterial hypertension.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CD8 T cells exert a critical role in the transition from left heart failure to lung remodeling and right ventricular hypertrophy
Authors: Wang Dongzhi , Weng Xinyu , Yue Wenhui , Chen Yingjie
Published: June 2021

Background

Patients with left ventricular (LV) failure or heart failure (HF) often progress to right ventricular (RV) hypertrophy and/or failure even with optimal medical care. Previously, we have shown a potential role for regulatory T cells (Tregs) in suppressing LV failure progression. However, the particular leukocyte subset(s) that promote the transition from LV failure to RV hypertrophy and failure are unknown. Here, we investigated the role of cytotoxic CD8+T cells in this progression.

Methods

Mice with LV failure produced by transverse aortic constriction (TAC) were randomized to depletion of cytotoxic CD8+T cells using specific blocking antibodies. The cardiac function, lung inflammation, fibrosis, vascular remodeling, and right ventricular remodeling were determined.

Results

LV failure caused lung inflammation and lung T cell activation involving both CD4+and CD8+T cell activation. Depletion of CD8+ T cells dramatically attenuated the increase of lung weight, lung inflammation, lung vascular remodeling, and RV hypertrophy in mice with existing LV failure.

Conclusions

Our findings demonstrate that CD8+T cells play a critical role in promoting the transition from LV failure to lung remodeling and RV hypertrophy, indicating that modulation of CD8+T cell activity may represent a new approach to heart failure therapy.

Support or Funding Information

This study was supported by research grants 81470512 and 81570355 from Nature Science Foundation, and Grants HL098669, HL102597, R01HL105406 from the National Institutes of Health, and a grant in aid from American Heart Association.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
EFFECTS OF RADIATION ON CUTANEOUS MICROVASCULAR FUNCTION IN THE INTACT HUMAN CIRCULATION
Authors: Banister Heather R , Parr Shannon K , Turpin Vanessa‐Rose G , Ade Carl J
Published: June 2021

Radiation is a commonly used treatment for various types of cancer, however it is often associated with an increased risk of cardiovascular disease (CVD). Previous animal studies have shown a significant decreased relaxation in irradiated arteries in response to Acetylcholine. However, there is a paucity of knowledge on the effects of radiation within the intact human circulation. Given that changes vascular function occurs early in the progression of numerous cardiovascular and metabolic diseases characterization of the microvascular responses to radiation treatment is critical. Therefore, the primary was to determine the effects of cancer treatment radiation on cutaneous microvascular reactivity in breast cancer patients.

METHODS

The present study utilized a longitudinal study design in breast cancer patients receiving radiation therapy. Cutaneous microvascular reactivity to Acetylcholine (ACh) was evaluated following radiation exposure in breast cancer patients at the site of radiation treatment and at a control non‐irradiated site. Briefly, red blood cell flux was measured as an index of cutaneous blood flow via laser Doppler flowmetry with ACh mediated vasodilation determined by iontophoresis drug delivery. Data are expressed as cutaneous vascular conductance.

RESULTS

To date, 4 patients have completed the study (planned enrollment of 15 patients). Cutaneous vascular conductance to ACh was significantly attenuated following a total cumulative dose of 1950 ± 719 cGy. Similarly, the total ACh response was decreased in the radiated tissue. The forth coming patients will provide additional insight into the effects of radiation exposure on microvascular reactivity. Furthermore, we will be able to provide insight into the role coexisting risk factors of metabolic syndrome and preexisting atherosclerosis on radiation‐induced vascular dysfunction.

CONCLUSION

This study demonstrates that low doses of radiation for cancer treatment attenuate cutaneous microvascular function, which may have long‐term implications for cardiovascular health in these patients.

Support or Funding Information

N/A

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Post‐Exercise Oxygen Uptake and Muscle Oxygenation in Pediatric Heart Transplant Recipients
Authors: Kosokowsky Kylee , Boyes Natasha G , Lahti Dana S , Blushke Corey R , Marciniuk Darcy , Butcher Scotty J , Erlandson Marta C , Wright Kristi D , Pockett Charissa , Tomczak Corey R
Published: June 2021

Pediatric heart transplant recipients (HTR) have reduced exercise tolerance and peak oxygen uptake (VO2) values are 57–73% of age‐predicted norms. Slow post‐exercise VO2 and muscle oxygenation recovery are related to exercise intolerance. However, despite clear exercise tolerance limitations and post‐exercise fatigue, VO2 and muscle oxygenation during recovery responses are unknown in this population.

Purpose

We tested the hypothesis that both post‐exercise VO2 recovery and muscle oxygenation recovery would be slower after peak exercise in pediatric HTR compared to controls.

Methods

Five pediatric HTR (mean ± SD age = 10.6 ± 3.0 years) and six healthy controls (age = 11.7 ± 2.7 years) performed cycle ergometry to peak exercise followed by 5 minutes of 20‐W cycle recovery. Pulmonary VO2 and muscle oxygenation (vastus lateralis tissue oxygenation index, TOI using near infrared spectroscopy) were sampled continuously during exercise and recovery. Data were linearly interpolated to 1‐s intervals, and both VO2 and TOI data were averaged into 5‐s and 10‐s time bins, respectively. VO2 recovery data were mono‐exponentially curve‐fitted to yield a recovery time constant (tau). TOI recovery was normalized from 0% (end exercise) to 100% (5 min post‐exercise) and data analyzed at set time points to characterize TOI time course changes (0s, 15s, 30s, 60s, 90s, 120s, 180S, 240s, and 300s). Statistical analyses included independent t‐tests for VO2 data and a between‐within (2 × 9, group × time) factorial ANOVA for TOI time course changes. Significance was accepted at p< 0.05.

Results

Recovery VO2 tau was significantly slower in pediatric HTR compared to healthy controls (68 ± 17 vs. 47 ± 12 s, respectively; p=0.044). There was a significant group × time interaction for TOI recovery (p=0.003) where TOI in HTR was significantly lower compared to controls at 15s (8 ± 8 vs. 46 ± 19%; p=0.003), 30s (22 ± 13 vs. 91 ± 31%; p=0.001), and 60s (47 ± 23 vs. 117 ± 36%; p=0.005). TOI was not statistically different between groups by 90s onwards (all p>0.05).

Conclusions

Post‐exercise VO2 and TOI recovery are prolonged in pediatric HTR compared to healthy controls. These findings suggest that non‐cardiac factors may contribute to the excessive recovery time following peak exercise in pediatric HTR.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Is Arterial Stiffness Increased in Pediatric Heart Transplant Recipients?
Authors: Singh Shreya , Blushke Corey R , Boyes Natasha G , Lahti Dana S , Kosokowsky Kylee , Marciniuk Darcy , Butcher Scotty , Erlandson Marta C , Wright Kristi D , Pharis Scott , Pockett Charissa , Tomczak Corey R
Published: June 2021

Adult heart transplant recipients (HTR) have increased arterial stiffness, despite resolution of the underlying pre‐transplant diagnosis. The impaired vascular function may also contribute to the reported impaired exercise tolerance in these patients. Patient age and the duration and sequela of the pre‐transplant cardiovascular disorder significantly contribute to the increased arterial stiffness observed in adult HTR, while the direct role of immunosuppressive therapies is less understood. We tested the hypothesis that despite young age, pediatric HTR will display increased arterial stiffness owing to their significant pre‐transplant cardiovascular disease and post‐transplant physical inactivity. We also tested the hypothesis that arterial stiffness would be related to exercise tolerance (peak oxygen uptake, VO2).

METHODS

Six pediatric HTR (3 females and 3 males; 10 ± 3 years) and 12 age‐ and sex‐matched healthy controls (6 females and 6 males; 10 ± 2 years) were studied. Carotid‐radial pulse‐wave velocity by ECG‐gated sequential applanation tonometry was used to determine arterial stiffness. HTR subjects also completed a peak VO2 test by cycle ergometry. Data were analyzed through an independent samples t‐test with significance differences being accepted at P < 0.05.

RESULTS

Pulse wave velocity was not different between HTR (8.50 ± 1.93 m/s) and the healthy controls (8.55 ± 1.52 m/s, P = 0.951). In addition, pulse wave velocity was not related to peak VO2 in HTR (r = −.529, P = 0.140).

CONCLUSION

Unlike in adult HTR, pediatric HTR have normal arterial stiffness compared to healthy‐matched controls, and arterial stiffness was not related to peak VO2 in this pediatric population. These findings suggest that the pre‐transplant diagnosis sequela do not unfavorably alter arterial stiffness in young pediatric HTR and that reduced peak VO2 in pediatric HTR is not related to arterial stiffness.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Retrograde and Oscillatory Shear Remain Stable Across the Menstrual Cycle but Increase in Postmenopausal Women
Authors: Somani Yasina B , Kim Danielle Jin‐Kwang , Barrett Megan A , Ogot Akinyi , De Souza Mary Jane , Proctor David N
Published: June 2021

Patterns of conduit artery shear are an important determinant of vascular function and increases to retrograde and oscillatory shear are associated with endothelial dysfunction, a key antecedent to atherosclerosis and cardiovascular disease. The adoption of this pro‐atherogenic profile described in humans is linked to chronological aging, and more recently, reproductive aging in women. To assess the potential influence of acute and chronic estrogen deficiency on arterial shear patterns, we studied premenopausal women (n=8, 22 ± 2 years) during the early follicular (Estradiol: 27.7± 9.2 pg/mL) and late follicular phase (Estradiol: 173.7 ± 144.3 pg/mL) of the menstrual cycle, and postmenopausal women (n=14, 60 ± 2 years, Estradiol: 22.3 ± 5.9) who were not on hormone therapy. Resting measures of brachial artery blood velocity and diameter were collected with Doppler ultrasound to determine mean, antegrade, and retrograde shear rates. Oscillatory shear index (OSI) was determined as the ratio between retrograde and antegrade shear rate. In premenopausal women, retrograde shear (−8.1 ± 2.8 vs. −7.6 ± 2.7 s−1, p=0.67) and OSI (0.07 ± 0.02 vs. 0.06 ± 0.03 a.u., p=0.89) were similar between menstrual phases, however these measures during both phases were significantly lower than in postmenopausal women (−13.3 ± 5.1 s−1, 0.21 ± 0.12 a.u., both p<0.05). These findings suggest that patterns of brachial artery shear remain stable across the menstrual cycle, despite fluctuations in estradiol. However, with prolonged estrogen deficiency secondary to menopause, retrograde and oscillatory shear are increased in the brachial artery, which likely contribute to endothelial dysfunction in postmenopausal women.

Support or Funding Information

Penn State Jaffe Endowement

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Smooth muscle‐selective ablation of A‐kinase anchoring protein 150 (AKAP150) mitigates diabetes‐induced cardiac dysfunction
Authors: Zhang Deqing , Brittian Kenneth R , Bhatnagar Aruni , Nystoriak Matthew A
Published: June 2021

Inadequate blood flow to the myocardium due to microvascular dysfunction may play a role in the development and progression of diabetic cardiomyopathy, although contributing mechanisms are poorly understood. Hyperglycemia, a hallmark of diabetes mellitus, promotes enhanced arterial tone via altered excitation‐contraction and ‐transcription coupling that is dependent upon kinase/phosphatase targeting to the membrane of vascular smooth muscle by the A‐kinase anchoring protein AKAP150. In this study, we tested the hypothesis that AKAP150‐dependent signaling in smooth muscle contributes to cardiac dysfunction in an experimental model of diabetes. We generated smooth muscle selective AKAP150‐null animals by crossing AKAP5‐floxed mice (Akap150fl/fl) with knock‐in mice expressing Cre recombinase under the control of SM22α (smCre). Offspring (AKAP150fl/fl‐smCre) were viable and demonstrated genetic recombination and loss of AKAP150 protein in vascular smooth muscle (aortic smooth muscle, mesenteric arteries, coronary arteries), but not in heart or brain tissues. Male AKAPfl/fl and AKAPfl/fl‐smCre animals (8–12 weeks) were maintained on a high fat/high sucrose (HFHS) diet for 20 weeks. Body weight and blood glucose (fasting and non‐fasting) were significantly elevated in HFHS groups compared to control chow‐fed animals at time points after 8 weeks. At 20 weeks, echocardiography revealed that AKAP150fl/fl animals on HFHS diet had significantly greater end systolic volume, as well as reduced ejection fraction and fractional shortening when compared to AKAP150fl/fl mice maintained on control diet for the same period. However, no significant differences in cardiac function or chamber dimensions were observed between AKAP150fl/fl‐smCre animals on HFHS versus AKAP150fl/f‐smCre animals on control diet. Our results suggest that AKAP150‐mediated signaling in vascular smooth muscle may contribute to altered cardiac function in a HFHS model of diabetes.

Support or Funding Information

This work was supported in part by grants from the National Institutes of Health (GM103492, HL142710) and American Heart Association (16SDG27260070),

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of the LPC‐ATX‐LPA Axis in the Development of Endothelial Dysfunction
Authors: Janovicz Anna , Kerkovits Nora Melinda , Majer Aliz , Balogh Lili , Balogh Andrea , Tigyi Gabor Joseph , Benyo Zoltan , Ruisanchez Eva
Published: June 2021

Introduction

Lysophosphatidylcoline (LPC) is a bioactive lipid component of low‐density lipoprotein (LDL) that plays an important role in the development of atherosclerosis. Based on literature data, LPC causes endothelial dysfunction through decreasing NO bioavailability, however, the underlying mechanisms are not completely understood. LPC can be hydrolyzed into LPA by the cell secreted enzyme, autotaxin (ATX). Our aim was to investigate the role of the LPC‐ATX‐LPA axis in the development of endothelial dysfunction.

Methods

Myographic measurements were performed on thoracic aorta segments isolated from male, adult C57/Bl6 mice. We examined the effect of 18:1 LPC (10 μM) on the NO‐dependent vasorelaxation after a 20 min incubation. The vessels were pre‐contracted with phenilephrine (PE), subsequently increasing concentrations of acetyl‐choline (ACh) were added to evoke vasorelaxation. Some of the vessels were pre‐treated with the ATX inhibitor BMP‐22 (10 μM) or the LPA1,3 antagonist Ki16425 (10 μM). FS‐3 substrate assay was used to measure ATX activity of the aortic tissue.

Results

LPC significantly attenuated ACh‐induced vasorelaxation without influencing the effect of the NO‐donor sodium nitroprusside. Interestingly, LPC‐induced suppression of the endothelium‐dependent vasorelaxation was more severe in the proximal, than the distal aorta that is more prone to develop atherosclerotic plaques. The ATX inhibitor BMP‐22 decreased the endothelial dysfunction and its protective effect was proved to be more pronounced in the proximal as compared to the distal segments. In addition, FS‐3 assay measurement for ATX activity showed higher activity in the proximal, than the distal part of the aorta. The LPA1,3 receptor inhibitor Ki16425 also reduced the effect of LPC in the proximal but not in the distal aorta.

Conclusions

Our study shows that ATX and LPA are involved in LPC‐induced endothelial dysfunction. The results suggest that in this process LPA acts through LPA1 and / or LPA3 receptors. According to the literature the development of atherosclerosis is faster and more severe on the proximal segment of the thoracic aorta, therefore the LPC‐ATX‐LPA system is likely to contribute to the progression of the disease.

Support or Funding Information

Supported by the Hungarian NRDIO (OTKA K‐112964, K‐125174 and NVKP_16‐1‐2016‐0042) as well as by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Molecular Biology thematic programme of the Semmelweis University and by the EFOP‐3.6.3‐VEKOP‐16‐2017‐00009 grant.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Microbiome Product Urolithin A Abolishes TGFβ‐Dependent Stimulation of PAI‐1 in Renal Epithelial Cells
Authors: Chappell Mark C , Pingue Georgia , Pirro Nancy , Tallant Ann , Gallagher Patricia
Published: June 2021

Introduction and Hypothesis

Ellagitannins are abundant in various foods including fruits, nuts and wines, as well as plant‐based supplements. Urolithin A is derived from ellagitannins metabolism by the microbiome, is absorbed by the gut epithelium and may significantly contribute to the biological actions of ellagic acid. Previous studies demonstrate renal protective effects of both ellagic acid and urolithin A; however, the cellular mechanisms that underlie the benefits of urolithin A are unclear. Activation of the renal TGFβ‐PAI‐1 pathway is a key cellular event that contributes to fibrosis, oxidative stress and progressive kidney injury. Therefore, the current study assessed the effects of urolithin A on TGFβ‐induced stimulation of PAI‐1 in renal proximal tubule (PT) cells. We hypothesized that urolithin A would present protective effects to attenuate PAI‐1 expression in PT cells and exhibit greater potency than the parent compound ellagic acid.

Results

We initially determined an optimal dose of TGFβ (0.1 to 10 ng/ml) to stimulate PAI‐1 release in the NRK‐52e cell line. Cells were maintained in serum free conditions for 48 hours prior to TGFβ treatment. At a concentration of 5 ng/ml, TGFβ increased PAI‐1 approximately 5‐fold (480 ± 35%, n=4; p<0.01) above unstimulated or basal levels following a 24 hour exposure. As expected, pretreatment with the TGFβ receptor (TGFβR) kinase inhibitor SB431542 (1 uM) abolished the increase in PAI‐1. Moreover, the EGFR kinase inhibitor AG1478 (1 μM) completely abrogated the PAI‐1 release in response to TGFβ and confirms earlier reports that TGFβ stimulation of PAI‐1 reflects the complete dependence on activation of the EGFR. In contrast, the cSRC kinase inhibitor SU6056 failed to block PAI‐1 release suggesting that TGFβ stimulates the ligand‐dependent transactivation of EGFR rather than direct cSRC activation of the EGFR. Similar to TGR and EGFR inhibition, pretreatment of the cells with urolithin A (40 μM) abolished the increase in PAI‐1 to TGFβ (5 ± 4% of basal release, n=4). Dose response studies of urolithin A revealed an ED50 of 22 ± 3 μM (n=3) to inhibit PAI‐1. Ellagic acid also inhibited TGFβ stimulation of PAI‐1 release, but was less potent (ED50 >50 μM) than Urolithin A.

Conclusion

We conclude that the protective effects of urolithin A may involve inhibition of the TGFβ‐EGFR‐PAI‐1 pathway in renal epithelial cells. Although the precise inhibitory mechanisms are presently unknown, urolithin A may potentially target either TGFβR‐ or EGFR‐dependent kinases to abrogate PAI‐1 expression.

Support or Funding Information

AHA Transformative Grant 18TPA34170522; Anonymous Contribution 15‐01401

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Modulation of gut microbiota by cyanidin 3‐glucoside in a mouse model of fatty liver disease
Authors: Wu Shusong , Liu Jie , He Ziyu , Tan Jijun , Liu Ming , Hou De‐Xing , He Jianhua
Published: June 2021

Recent studies suggested that the dysbiosis of gut microbiota might be a leading cause of nonalcoholic fatty liver disease (NAFLD), and our previous study revealed that Lonicera caerulea L. berry, which is rich in cyanidin 3‐glucoside (C3G), has protective effects against high fat diet (HFD)‐induced fatty liver disease. The present study aimed to investigate the regulatory effect of C3G on gut microbiota in a mouse NAFLD model. C57BL/6N mice (n=4 for each group) were fed a normal diet (Research Diets D12450B), HFD (Research Diets D12492) only, or HFD containing 0.4% of C3G for 3 months based on our pilot test, liver sections were stained by hematoxylin–eosin, serum lipids and transaminases were measured with the automatic biochemical analyzer, and cecal microbiota was characterized by high throughput sequencing of 16S rDNA amplicons. Dietary supplement of C3G decreased fat deposition and improved liver histology in mice. Biomedical analysis indicated that C3G significantly decreased the ratio of low density lipoprotein cholesterol (LDL‐c) to high density lipoprotein cholesterol (HDL‐c), the level of triacylglycerol, and levels of transaminases including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of HFD‐fed mice. The analysis of high throughput sequencing data revealed that the relative abundance of Firmicutes was increased by HFD, but decreased by supplementing C3G; in addition, C3G increased the relative abundance of Bacteroidetes at the phylum level. Most notable microorganisms at the genus level were Lactococcus, Romboutsia and Clostridium; in particular, HFD increased the relative abundance of Lactococcus and Romboutsia, but decreased Clostridium, on the contrary, C3G inhibited Lactococcus and Romboutsia, but promoted the growth of Clostridium. These data demonstrated that C3G potentially attenuated HFD‐induced fatty liver disease by modulating gut microbiota especially up‐regulating Clostridium and down‐regulating Lactococcus and Romboutsia.

Support or Funding Information

This work was partially supported by National Natural Science Foundation of China (No. 31741115) and Hundred Talents Program of Hunan Province.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of the Speed of Body Weight Loss on Body Composition Changes and Energy Density for Body Weight Loss in Exercised Rats
Authors: Kitaguchi Mizuki , Maeda Megumi , Okamura Koji
Published: June 2021

We examined the effects of the speed of body weight (BW) loss on changes in the body composition and energy required for BW loss in exercised rats. Rats (average BW: 275 g), were divided into a rapid weight reduction group (Rapid, n = 5), which was fasted for 3 days, and a slow weight reduction group (Slow, n = 5), which had their food restricted for 17 days in order to achieve comparable BW loss to the Rapid group. The rats were placed individually into a metabolic chamber with a 1‐m ladder inside. The water bottle was set at the top of the chamber, forcing the rats to climb the ladder to drink. The BW loss was −42.7 g (standard deviation [SD] 4.2) in the Rapid group and −43.8 g (SD 4.9) in the Slow group. The total energy expenditure was 95.1 kcal (SD 10.7) in the Rapid group and 555.6 kcal (SD 69.3) in the Slow group. Since the metabolizable energy was 0 kcal in the Rapid group and 521.1 kcal (SD 44.9) in the Slow group, the energy deficit was −95.1 kcal (10.7) in the Rapid group and −34.5 kcal (72.7) in the Slow group. Therefore, the energy density for BW loss by 1 kg was not significantly different between the Rapid group (2246 kcal [SD 320.3]) and the Slow group (734.6 kcal [SD 1631.6]). The estimated changes in the lean tissue (LT) and adipose tissue (AT) based on the energy density of LT (1.25 kcal/g) and AT (7.6 kcal/g) and the energy deficit did not differ significantly between the groups (LT: −36.0 g [SD 5.4] and AT: −6.8 g [SD 1.9] in the Rapid group and LT: −47.1 g [SD 11.8] and AT: 3.3 g [SD 11.6] in the Slow group). Therefore, the speed of BW loss had no marked effect on the changes in the body composition and energy required for BW loss in exercised rats. However, the increase in the AT observed in the Slow group is theoretically unlikely, suggesting the overestimation of energy intake (metabolizable energy) due to a decrease in the absorption rate or an increase in the energy density in the AT in this group.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RhoA and MAPK Pathway in Toxin‐induced Production of TNF‐α during Clostridium difficile Infection
Authors: Sun Xingmin , Wang Shaohui , Feng Hanping
Published: June 2021

Release of proinflammatory cytokines or other mediators from immune cells or intestinal epithelial cells is a critical activation event in C. difficile toxin‐mediated intestinal inflammation. In this study we investigated the role of TNF‐α in the pathogenesis of CDI using mouse model of toxin exposure or CDI, and dissected the roles of RhoGTPase and MAPK in TcdA‐induced production of TNF‐α by macrophages. We showed that inactivation of RhoA by TcdA activates p38 and ERK, which controls of TNF‐α production by macrophage Raw264.7 cells. We also demonstrated that calcium signaling regulates TcdA‐induced TNF‐α in macrophage cell line. Based on these findings we propose that inhibition of p38 and ERK activation may be beneficial in reducing inflammatory symptoms in patients with CDI by blocking toxin‐induced TNF‐α release.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Holistic Neuro‐Physio Quanta Coherence‐Congruence Energy Dynamics for Exploring the Cause and Symptoms of Diseases
Authors: Tulp Orien L , Einstein George P , Rahman Michael S , Konyk Carla M
Published: June 2021

Dynamic Congruence and Coherence is a dynamic model and framework used to understand the mathematical and quanta relationships within the biochemical and biophysical aspects of the human organism. It is an integrated or holistic model that may be utilize to explore the etiology and the observed signs and symptoms of the diseased and healthy states (stable and unstable states) With measured parameters, the model can then be used to predict which of the parameters or symptom or system disruption may have the largest influence on Dynamic Congruence and thus explore significant avenues into potential therapeutic targets. The sign and symptoms represent our Quanta or information output.

This Energy model also lends to graphical representation of our body as a physiologically dynamic system, as well as an input model for the deliverance of Quanta to that system.

In the model, several parameters of various systems, with appropriate correction and correlation factors, summate to provide a description of dynamic congruence. If an organism is in a state of dynamic congruence, we expect that changing one parameter will influence another parameter to change in the opposite direction, so that the equilibrium is restored. Mathematically, this means that the system will revert back to the original number, also it would suggest that the organism is a congruent system that moves away from chaos and disorder.

As the spring‐like structures in figure 1 and the qualifier ‘dynamic’ suggest, it may take the system a while before it ‘swings back’ into the original state, thus representing a truly holistic model.

Support or Funding Information

Support from Institutional Resources of USAT, EMI, and UHH

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Lipid Metabolism at Two Different Walking Speeds in Obese Individuals: Pilot Study
Authors: Choi Myung Dong , Taylor Trent D
Published: June 2021

Exercise is an important factor of obesity and overweight management. American College of Sports Medicine recommends that 150–250 minutes per week and up to 60 minutes per day of moderate‐intensity aerobic exercise should be performed for weight gain prevention or modest weight reduction. Walking is a common and relatively safe form of aerobic exercise that can easily be incorporated into weight management programs. The energy expenditure associated with walking has been reported to be either linearly or slightly exponentially related to speed. Thus, interval walking training has been developed as a novel free‐living training modality that improves physical fitness and cardiovascular risk factors in humans.

PURPOSE

to determine if an interval walking exercise increases fat breakdown, fat utilization, and energy expenditure to a greater extent, compared with constant walking exercise in obese adults.

METHODS

This study was set as randomized crossover design. Six sedentary obese individuals (BMI ≥ 30 kg/m2 and 18–50 yrs) were recruited. Initially six subjects were randomly assigned into a constant speed walking group (CON) or an interval walking group (INT). Then, CON became INT and INT became CON. The constant speed walking consists of a single bout of 40 min walking exercise at 45% of VO2max on a treadmill. The interval walking consists of a single bout of 40 min walking exercise with cycles of alternating 3‐min slow (30% of VO2max), 3‐min moderate (45% of VO2max), and 3‐min fast (60% of VO2max) walking. Energy expenditure and fat usage were measured at rest and every 10min during walking exercises via indirect calorimetry. Blood samples were drawn at rest and every 10min during walking exercises to measure glycerol levels. Two‐way ANOVA was used to determine differences in energy expenditure and fat utilization between the groups.

RESULTS

The net rates of fat utilization (g/min) and calorie expenditure (kcal/min) were not different between the groups during walking exercises. Also, blood glycerol concentrations were not different between the groups at any time points of exercise. However, the net rates of fat utilization, calorie expenditure, and blood glycerol concentrations were significantly higher at 30min and 40min of exercise, compared to those at 10min of exercise in both groups.

CONCLUSION

Our data show that walking speeds might not be a primary factor to regulate fat utilization and energy expenditure during low and moderate exercise intensities. However, an increase in fat metabolism and energy expenditure during walking exercises may be attributed to the longer duration of exercise. Thus, these findings may provide a better exercise strategy to increase lipid breakdown and prevent weight gain in overweight/obese people.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Proteolytic Cleavage by House Dust Mite Impairs SPLUNC1's Ability to Modulate TH2 Inflammation in the Airway
Authors: Wu Tongde , Tarran Robert
Published: June 2021

Lung epithelial cells are often on of the first lines of defense against inhaled allergens. They also work in concert with other airway cell types to orchestrate innate immune responses, keeping inflammation under control. In allergic asthma, allergens (e.g., HDM) disrupts the normal barrier function of epithelia, as well as its interaction with other airway cells via various mechanisms. Proteolytic enzyme activity of allergen components is thought to be one of top contributors of allergic inflammation in the lung. A large body of evidence supports that the biologic activity of HDM proteases augment allergic activity by 1) directly promoting IgE synthesis; 2) damaging the lung epithelium, increasing bronchial permeability; 3) degrading epithelial tight junctions and increasing accessibility to dendritic antigen presenting cells that lie beneath the epithelium; and 4) causing the release of pro‐inflammatory cytokines from epithelial cells, mast cells and basophils.

Short palate, lung and nasal epithelial clone 1 (SPLUNC1) is a 256‐amino acid, secretive protein in polarized epithelia and is present at high levels in normal airway surface liquid (ASL). SPLUNC1 is a multi‐functional protein, which regulates ion channel activity, has anti‐microbial activity and affects surface tension. We observed that 1) SPLUNC1 is reduced in asthmatic patients' sputum as well as HDM challenged human bronchial epithelial cells (HBECs). 2)SPLUNC1 was degraded by HDM in both time‐ and dose‐ dependent manners. 3) SPLUNC1 knockout (KO) mice showed more severe inflammatory phenotypes in their airways when challenged with HDM, compared to their wildtype (WT) littermate controls.

Overall, we conclude that SPLUNC1 is an epithelial‐derived factor that plays a major role in dampening TH2 inflammation in airways, which is deranged in asthma patients. SPLUNC1 deficiency is partially due to its proteolytical cleavage by HDM. Identifying strategies to increase SPLUNC1 resistance to HDM proteolytic activities or SPLUNC1 in ASL may lead to novel therapies to treat allergic asthma.

Support or Funding Information

American Asthma Foundation NCCU‐DUKE CTSI

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibition of Nitric Oxide Synthesis Eliminates Interstitial Adenosine Production During Systemic Hypoxia in Rat Skeletal Muscle
Authors: MacLean David , Fabris Sergio , Bernardo Ashley
Published: June 2021

The purpose of this study was to examine the relationship between nitric oxide (NO) synthesis and adenosine (Ado) production in the interstitial space of skeletal muscle during systemic hypoxia. In order to accomplish this, microdialysis fibers were inserted into the hindlimb of anesthetized rats and perfused with the following solutions; 1) Ringer's (control), 20 mM SNP (NO donor), 10 mM L‐NAME (NO inhibitor), 500 μM AOPCP (Ado inhibitor) and 10 mM L‐NAME+ 500 μM AOPCP during baseline (100% O2) and hypoxia (10.5% O2). Ringer's perfusion did not result in any changes in interstitial NO concentrations during either baseline or hypoxia. The perfusion of L‐NAME, AOPCP and L‐NAME+AOPCP inhibited (p<0.05) NO production below detection limits, while SNP perfusion increased interstitial NO levels beyond detection limits throughout the experiment. During Ringer's perfusion, interstitial Ado concentrations were increased (p<0.05) during hypoxia (0.07±0.01) and decreased (P<0.05) during recovery (0.05±0.01 μM) as compared to baseline (0.04±0.01 μM). The perfusion of L‐NAME, AOPCP and L‐NAME+AOPCP all inhibited adenosine production to the point where interstitial Ado levels were below detection limits (p<0.05) during baseline, hypoxia and recovery. Surprisingly, the perfusion of SNP also dramatically decreased (p<0.05) the interstitial adenosine concentrations below detectable limits during hypoxia (undetectable) and recovery as compared to baseline. These data demonstrate that interstitial Ado production is very closely linked to NO availability and even under conditions when interstitial Ado production is stimulated (hypoxia), blocking NO availability completely eliminates all interstitial Ado production. These data further indicate that interstitial Ado production is tightly regulated within a narrow range of NO concentrations and a static pool of NO is required for normal interstitial Ado production.

Support or Funding Information

Supported by NSERC

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.