bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Modulation of Adipose function: Role of Endothelial Argonaute 1
Authors: Chen Zhen , Tang Xiaofang , Miao Yifei , Qi Zhijie , Luo Yingjun , Sriram Kiran , Van Keuren‐Jensen Kendall , Fueger Patrick , Wang Qiong , Yeo Gene , Zhong Sheng 
Published: June 2021

Among all individuals with Type 2 diabetes mellitus (T2DM), 80% are obese. The dramatic expansion of adipocytes can give rise to chronic hypoxia, poor blood perfusion, accumulation of pro‐inflammatory cytokines, all of which contribute to insulin resistance, key feature of T2DM. Lining the inner surface of microvessels, endothelial cells (ECs) respond to alterations in oxygen, metabolites, and growth factors to further modulate adipose function. However, the molecular and cellular mechanisms underlying the EC‐adipose crosstalk remain largely unknown and have recently attracted great research interests. In this study, we investigated the role of microvascular ECs in adipose function in the context of obesity and insulin resistance. Specifically, we examined the role of microRNA (miR)‐mediated gene regulation in the endothelial modulation of adipose function.We first used cross‐linking and immunoprecipitation sequencing (CLIP‐seq) to profile the miR targetome in ECs subjected to hypoxia, to which the EC response is often compromised in obesity. CLIP‐seq revealed a panel of angiogenic inhibitors, including thrombospondin‐1 (THBS1; which is positively associated with obesity and insulin resistance) were enriched in miR‐induced silencing complex in ECs under hypoxia. However, their expression was drastically suppressed in ECs by hypoxia. Ina murine T2DM model, mice with EC‐specific AGO1‐knockout (EC‐AGO1‐KO) exhibited a lean phenotype, with lower body weight and fasting glucose level and higher insulin sensitivity, as compared to their wild‐type littermates. The EC‐AGO1‐KO animals also had less body fat content, particularly in the subcutaneous and brown adipose tissues. Histological analysis and RNA‐seq demonstrated that EC‐AGO1‐KO possess higher angiogenic and browning activity and lower inflammation in the adipose depots. Overexpression of THBS1 abolished the protective effect of AGO1 in the subcutaneous tissues, suggesting that AGO1‐KO‐mediated metabolic benefit is in part through suppression of THBS1.Collectively, these results support a mechanism by which ECs, through AGO1‐mediated miR‐targetome modulate adipose function and metabolic states. Our study provides novel insights linking endothelial function and adipose tissue remodeling. Further, given that endothelial function is often compromised in T2DM, the molecular mechanisms underlying the endothelium‐adipocyte crosstalk may offer new approach to manage metabolic disruption associated with obesity and diabetes.Support or Funding InformationK99/R00HL122368This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cholesterol Inhibits H2S‐Mediated Vasodilation
Authors: Mendiola Perenkita J , Gonzalez Bosc Laura V , Naik Jay S , Kanagy Nancy L 
Published: June 2021

Hydrogen sulfide (H2S), the most recently described endothelium‐derived vasodilator, is predominantly produced in the endothelium by cystathionine γ‐lyase (CSE). We previously demonstrated that within endothelial cells (ECs), H2S‐mediated vasodilation involves activation of transient receptor potential cation channel subfamily V member 4 (TRPV4)‐dependent Ca2+ influx and large conductance Ca2+‐activated potassium (BK) channel. In addition, a single concentration of H2S donor NaHS (1 μM) dilated small mesenteric arteries (<100 μm) but had no effect in large mesenteric arteries (>300 μm). Furthermore, inhibiting CSE generation of H2S with β‐cyanoalanine (BCA, 100 μM) impaired acetylcholine (ACh)‐induced dilation in small mesenteric arteries, but had no effect in large mesenteric arteries. These data suggest that H2S‐induced dilation is prominent and important in small resistance arteries but not in larger arteries. It is possible that decreased availability of TRPV4 and/or BK in larger arteries is responsible for the diminished sensitivity to H2S‐induced vasodilation. Previous reports suggest that membrane cholesterol negatively regulates TRPV4 mobility and BK activity. Our current study tested the hypothesis that H2S‐mediated vasodilation is inhibited by membrane cholesterol. Mesenteric arteries induced vasodilation was assessed in pressurized large rat mesenteric arteries (>300 μm). Isolated pressurized mesenteric arteries (320 μm – 360 μm) were pretreated luminally with vehicle (HEPES) or the cholesterol‐depleting agent, methyl β cyclodextran (MBCD, 100 μM) and exposed to NaHS (100 μM). NaHS‐induced dilation in U46619 pre‐constricted arteries was significantly enhanced by MBCD pretreatment (+vehicle: 6.78% ± 1.6, +MBCD: 17.10% ± 6.8, p < 0.05, n=3–4 animals/group). These studies suggest that membrane cholesterol disrupts H2S‐mediated vasodilation. Ongoing studies in isolated mesenteric arteries of different sizes are investigating endothelial cell membrane cholesterol content and the effect of cholesterol depletion on TRPV4‐dependent Ca2+ influx in large and small mesenteric arteries.Support or Funding InformationFunding provided by the NIH HL12330 & HL7736‐23This 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 Tissue Iron in Development of Cardiovascular Delayed Effects of Acute Radiation Exposure
Authors: Russell Abigail , Chittajallu Supriya , Siddiqui Sameen , Unthank Joseph L , Sampson Carol H , Fisher Alexa , Orschell Christie M , Miller Steven J 
Published: June 2021

The threat of radiation exposure from terrorist activity, warfare, or accidents creates an urgent need to develop agents to mitigate the acute and chronic effects of high dose rate total body irradiation (TBI). High level short‐term radiation exposure results in rapid organ injury leading to development of the acute radiation syndrome (ARS), which if untreated will result in death within weeks. Survivors of ARS will experience the delayed effects of acute radiation exposure (DEARE), which include development of chronic pathology and dysfunction of multiple organ systems months to years following exposure. However, the factors and mechanisms that regulate the onset and progression of cardiovascular DEARE are unclear. The goal of the current study was to determine the possible role for abnormal iron metabolism in the development of cardiac DEARE, especially vascular pathology. Studies utilized the ARS mouse model with gamma radiation exposure at 853 cGy (LD50) and time points from 1 day to 4 months post‐TBI.Serum iron was elevated at 1 day post‐TBI, peaked at 2 weeks, and returned to non‐irradiated control values by 4 weeks post‐TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number, hematocrit, and hemoglobin concentrations. Perls' Prussian Blue staining was used to detect iron (hemosiderin) deposition in heart paraffin‐embedded tissue sections, and myocardial iron was present as early as 2 weeks post‐TBI. Pretreatment of mice with the iron chelator deferiprone in drinking water decreased myocardial iron deposition (P=0.055), but not serum iron, at 2 weeks. A histological assessment of coronary artery endothelial cell (EC) density showed intimal nuclei per unit area significantly decreased as early as two weeks post‐TBI vs. non‐irradiated controls (P<0.05), and the decrease persisted to 4 months post‐TBI. EC density in deferiprone‐treated mice was significantly increased at 2 and 4 weeks post‐TBI compared to irradiated non‐treated mice (P<0.03). Administration of the ferroptosis inhibitor ferrostatin‐1 via daily i.p. injection for 2 weeks post‐TBI resulted in no change in coronary artery EC density compared to vehicle controls. Taken together, the results suggest the presence of tissue iron contributes to endothelial cell loss occurring early following TBI and is a significant event impacting the development of DEARE. This information may facilitate development of novel medical countermeasures to prevent or mitigate cardiovascular DEARE‐related pathophysiology.Support or Funding InformationNIH 1U01AI107340‐01 (C. Orschell), IUPUI Research Support Funds Grant (S. Miller)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Short‐term Ibuprofen Treatment cause Gender‐Specific Differences in Proteasomal and Mitochondrial functions in Mice Heart
Authors: Tiwari Shuchita , Gomes Aldrin 
Published: June 2021

Ibuprofen is the most common pain‐killer widely used for the management of dental pain, headache, migraine and rheumatoid arthritis. Concern has been raised due to adverse cardiovascular side effects associated with the chronic use of ibuprofen. Thus, understanding the short‐term effects of ibuprofen on cardiac function is crucial to the safe use of the drug among individuals with established cardiovascular disorders. The objective of this study was to evaluate whether ibuprofen caused gender‐specific differences in mitochondrial and proteasomal functions in mice cardiac tissue and to gain insights into the molecular mechanisms underlying these differences. To determine whether there is a sex difference on protein homeostasis with respect to ibuprofen treatment 8‐week‐old aged matched male and female C57BL/6J mice were treated with ibuprofen (100 mg/kg/day) dissolved in drinking water for seven days and were randomly assigned to control group and group treated with ibuprofen. Ibuprofen significantly reduced caspase‐like (β1), and trypsin‐like (β2) 26S proteasome activities in both male and female heart. However, ibuprofen reduced chymotrypsin‐like (β5 proteasome activity) in the female heart but not male hearts. Notably, immunoproteasome β1i (expression) and β5i (expression and activity) significantly increased in females relative to males. In contrast, a trend towards the decrease in expression of β2i and β5i immunoproteasome was observed in ibuprofen‐treated male mice. To determine mitochondrial function, measurement of mitochondrial respiratory chain complexes revealed that ibuprofen treatment significantly decreased complex I activity in female heart compared with males. Short‐term ibuprofen treatment also decreased heart weight in male mice but not in female mice. Western blots and oxyblots analysis showed no differences in the expression levels of polyubiquitinated proteins, free ubiquitins and oxidized proteins in both males and females. Our in vitro study with rat cardiac H9c2 cells showed that ibuprofen‐induced reactive oxygen species (ROS) generation, decreased mitochondrial complex II activity, reduced mitochondrial membrane potential and had variable effects on cell viability. In conclusion, our findings suggest that short‐term ibuprofen treatment results in gender‐specific adverse changes in cardiac mitochondrial function and protein homeostasis.Support or Funding InformationAmerican Heart Association (AHA) 16GRNT31350040 grant (A.V.G.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vascular Function in Heart Failure Patients Implanted with a Continuous‐Flow Left Ventricular Assist Device: Impact of Increasing Peripheral Vascular Pulsatility
Authors: Hydren Jay R. , Gifford Jayson R. , Jarrett Catherine L. , Park Soung Hun , Shields Katherine L. , Ratchford Stephen M. , Broxterman Ryan M. , Kithas Andrew C. , Thurston Taylor S. , Selzman Craig H. , Drakos Stavros G. , Richardson Russell S. 
Published: June 2021

Vascular function is thought to be attenuated in heart failure patients implanted with a continuous‐flow left ventricular assist device (LVAD), likely due to a decrease peripheral vascular pulsatility, which may contribute to the observed serious cardiovascular complications. However, the impact of increasing pulsatility on vascular function in this population is unknown.MethodsFifteen LVAD recipients and fifteen controls, matched for age and physical activity, underwent 45‐minutes of unilateral arm pulsatility treatment, evoked by cuff inflation, distal to the elbow, with a two second duty cycle. Vascular function was assessed by brachial artery flow mediated dilation (FMD, Doppler ultrasound).ResultsBaseline FMD, expressed as percent dilation, was not different between the LVAD recipients and controls (LVAD: 4.1±1.8; Controls: 4.1±1.5%), however, FMD/shear rate was significantly lower (LVAD: 0.10±0.04; Controls: 0.16±0.07) and time to peak dilation significantly longer in the LVAD group (LVAD: 77±21; Controls: 41±16s). The LVAD recipients exhibited a significantly attenuated pulsatility index (PI) compared to controls at baseline (LVAD: 3±2; Controls: 14±7), but experienced a similar PI during the pulsatility treatment (LVAD: 29±21; Controls: 33±15). Both % FMD (LVAD: 6.9±1.9; Controls 6.9±2.7%) and FMD/Shear rate (LVAD: 0.19±0.08; Controls 0.30±0.17) increased similarly in both groups with the pulsatility treatment, while time to peak was unaltered.ConclusionsLVAD recipients exhibit vascular dysfunction. Pulsatility treatment improved vascular function in both groups, but, most importantly, this intervention restored vascular function in the LVAD recipients to the baseline level of the controls, and may, through this improved vascular health, reduce cardiovascular complications in this population.Support or Funding InformationThis research was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award NIH 1T32HL139451 from the National Heart, Lung, and Blood Institute.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic Reductive Stress Impairs Endoplasmic Reticulum Function and Cause Proteotoxic Cardiac Disease
Authors: Soorappan Rajasekaran Namakkal , Shanmugam Gobinath , Wang Ding , Fernandez Jolyn , Jones Dean P , Abel Dale E , Ping Peipei 
Published: June 2021

BackgroundHeart failure (HF) is a growing cause of global human morbidity and mortality and elevated ROS are generalized as drivers of HF pathology. However, antioxidant treatments have failed to offer sufficient therapeutic benefits; the underlying mechanisms remain largely unknown. Here, we hypothesized that chronic reductive stress (cRS) induces endoplasmic reticulum (ER) dysfunction, which leads to proteotoxicity and pathological cardiac remodeling.MethodsTransgenic mice expressing cardiac specific, constitutively active Nrf2 (caNrf2‐TG) and their non‐transgenic (NTG) littermates at the age of 3 and ~6 months (n=6–8/group) were used to determine ER redox states and protein aggregation levels. Diastolic function was measured by echocardiography.ResultscRS substantially increased ER glutathione levels and suppressed protein oxidation (DMPO‐adducts) in TG vs. NTG mouse hearts. The co‐localization of KDEL (ER‐marker) with GSH or DMPO, showed by immunofluorescent imaging, indicates a hyper‐reductive redox milieu in the ER. Immunoblotting revealed a dose‐dependent induction of ER‐proteins (CHOP, GRP78, GRP94 and PDI) in TG hearts at 3‐months‐old. However, at 6‐months of age, this response was significantly repressed along with impaired protein folding response in TG mice, evidencing that progressive cRS is associated with a transition from adaptive ER stress‐response to ER dysfunction. Notably, electron micrograph and Proteostat® staining showed a dose‐ and age‐dependent augmentation of misfolded/aggregated proteins in TG hearts; these aggregates were highly ubiquitinated as demonstrated. Patterns of Mitral valve movement showed that ≥6 month‐old TG mice developed overt LV diastolic dysfunction as evidenced by increased mitral inflow velocity (MV E/A ratio).ConclusionER dysfunction and proteotoxic insults triggered pathological cardiac remodeling and diastolic dysfunction in the TG hearts experiencing cRS. The heterogeneity of redox profiles in HF subjects demands further investigation into the potential impact of RS in cardiovascular pathology. Research focusing on correlations between redox stress intensity, redox imbalance and disease progression may offer insights into redox‐based therapies.Support or Funding InformationThis study was supported by funding from NHLBI (HL118067), NIA (AG042860), the AHA (BGIA 0865015F), University of Utah Center for Aging Pilot grant (2009), the Division of Cardiovascular Medicine/Department of Medicine, University of Utah and the start‐up funds (for NSR) by Department of Pathology, the University of Alabama at Birmingham, AL and UABAMC21 grant by the University of Alabama at Birmingham, AL.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Short‐term changes in left ventricular dyssynchrony may lead to congestive heart failure
Authors: Castaneda Diana , Yamazaki Katrina 
Published: June 2021

Ventricular dyssynchrony is characterized by a difference in timing or lack of synchrony in ventricular contraction, leading to an inefficiency of pumping blood. Ventricular dyssynchrony (VD) consists of a disruption in the normal electrical conduction system, which leads to congestive heart failure (CHF). Long‐term effects of VD that lead to CHF is well studied but little is known about the short‐term effects associated with VD. Short‐term physiological changes due to VD are crucial because electrical and mechanical abnormalities or structural changes cause a decrease in overall cardiac functionresulting in long‐term effects that may lead to CHF. Such physiological abnormalities can range from metabolic alterations, metabolic remodeling such as changes in substrate utilization, mitochondrial dysfunction, ATP deficiency, impaired contractility, and the progression of cell regeneration and cell growth, etc. Thus, theobjective of this study is to investigate short‐term cellular effects associated of induced VD in vivo. Our hypothesis is that induced left ventricular dyssynchrony (via pacing) in a non‐CHF model may lead to short‐term changes such as alterations in cardiac metabolism and mitochondrial dysfunctionresulting in structural rearrangements. Frogs will undergo ventricular pacing to induce VD. Strain patterns associated with contraction and relaxation will be analyzed to verify dyssynchrony. Paced and non‐paced regions of the heart will be analyzed to determine if reactive oxygen species (ROS) generation and mitochondrial abnormalities lead to cellular changes that may induce apoptosis leading to structural rearrangement, known as ventricular remodeling.Support or Funding InformationSupported by Cal State LA Minority Opportunities in Research MBRS‐RISE Program fund through NIH NIGMS under Grant No. R25 GM61331.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evidence that Food Intake Controls Diurnal Blood Pressure Rhythm in Mice
Authors: Zhang Dingguo , Jin Chunhua , Speed Joshua , Pollock David M. 
Published: June 2021

Blood pressure exhibits a 24‐hour rhythm and peaks in the beginning of the active period in both human and rodents. Previous studies suggested that timing of food intake plays pivotal roles in regulating many physiological processes, such as lipid metabolism, sleep‐wake cycle, immune responsiveness, and even blood pressure. However, whether blood pressure and kidney function is altered by changing feeding time remains largely unknown. The current study was designed to test the hypothesis that feeding during the inactive period (reverse feeding or RF) disrupts blood pressure and kidney function in mice. Male C57Bl/6J mice (12–16 weeks old, n=6) were placed in metabolic cages and had free access to food and water for 3 days, followed by a 6‐day RF with free access to water. Food and water intake, as well as urine output were monitored twice per day at the beginning of active and inactive periods (AP and IP, respectively). Blood pressure was recorded via telemetry transmitters. As expected, we found that mean arterial pressure (MAP) was significantly higher in AP compared to IP when mice were fed ad libitum (114 ± 1 vs. 96 ± 1 mmHg, respectively, p<0.01). However, RF led to an inversion of diurnal MAP (98 ± 5 vs. 112 ± 2 mmHg, p=0.02). Similar effects were observed in heart rate (ad libitum, 659 ± 12 vs. 548 ± 16 bpm, p=0.03; RF, 484 ± 48 vs. 613 ± 22 bpm, p=0.02). In contrast, RF did not alter diurnal rhythm in urine output (ad libitum, 1.0 ± 0.2 vs. 0.2 ± 0.1 ml/12hr, p<0.01; RF, 1.4 ± 0.1 vs. 0.7 ± 0.1 ml/12hr, p<0.01). However, diurnal rhythm in urinary sodium excretion was dampened after RF (ad libitum, 7.3 ± 0.8 vs. 1.0 ± 0.2 mEq/12hr, p<0.01; RF, 6.5 ± 0.8 vs. 4.5 ± 0.7 mEq/12hr, p=0.08). Similarly, diurnal rhythm in urinary potassium excretion was abolished (ad libitum, 7.0 ± 0.9 vs. 0.8 ± 0.2 mEq/12hr, p<0.01; RF, 4.8 ± 0.7 vs. 5.3 ± 0.7 mEq/12hr, p=0.97). We also measured urinary excretion of aldosterone by ELISA and found that its diurnal rhythm remained intact after RF (ad libitum, 990 ± 142 vs. 370 ± 38 pg/12hr, p=0.01; RF, 856 ± 181 vs. 204 ± 42 pg/12hr, p=0.01). These data suggest that RF inverts diurnal blood pressure rhythm and differentially modifies diurnal excretion of water and electrolytes in mice.Support or Funding InformationFunded by an AHA pre‐doctoral fellowship (18PRE33990345) to DZ and NHLBI P01 HL136267 to DMP. We appreciate Drs. Celso and Elise Gomez‐Sanchez's help with the aldosterone assay.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.