bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperoxia exposure results in decreased expression of pro‐resolution receptor ALX/FPR2 (1153.12)
Authors: Cox Ruan , Phillips Oluwakemi , Fukumoto Jutaro , Fukumoto Itsuko , Arias Stephen , Cho Young , Lockey Richard , Kolliputi Narasaiah 
Published: June 2021

Rationale: Endogenously produced polyunsaturated fatty acids (PUFAs) are key mediators of the anti‐inflammatory response following acute injury. PUFAs such as resolvins and lipoxins have demonstrated potent pro‐resolutionary effects in acute lung injury. These molecules have been shown to bind and exert their effects through G‐coupled protein receptor Lipoxin A4/formyl peptide receptor 2 (ALX/FPR2). Previous reports suggest that various septic or sterile insults lead to an increase in ALX/FPR2 expression; however, the response of ALX/FRP2 to oxidative stress has not been elucidated. In this study, we investigated the role of ALX/FPR2 in a murine mouse model of hyperoxic acute lung injury (HALI).Methods: C57BL/6 mice were exposed to hyperoxic (50, 75, or 95% O2) or normoxic (≍ 21% O2) conditions for 24, 48, or 72hrs. Following atmospheric treatment, mice were euthanized; bronchoalveolar lavage (BAL) fluid and lung tissue were collected for analysis. BAL fluid was used to assess alveolar protein leak. Lung tissue samples were used for histopathological analysis and to assess ALX/FPR2 protein and RNA expressiton following hyperoxia treatment.Results: Results reveal that hyperoxia exposure results in a significant decrease in ALX/FRP2 expression in comparison to normoxia treated controls. This decrease was dose dependent and reduction in ALX/FRP2 was evident in as little as 24hrs following hyperoxia exposure. For the first time, our results reveal a significant decrease in ALX/FRP2 expression which has not been shown in other forms of acute lung injury.Conclusion: While the production of PUFAs in HALI may be normal, their pro‐resolutionary effects may be dampened due to the decrease in receptor expression.Grant Funding Source: Supported By: NIH RO1 HL105932
Aerosolized heparin mitigates chlorine‐induced lung injury (1153.15)
Authors: Basappa Susanna , Zarogiannis Sotirios , Yu Zhihong , Anjum Naseem , Rodriguez Cilina , Fernandez Solana , Honavar Jaideep , Clark Michael , Doran Stephen , Pittet Jean‐Francois , Matalon Sadis 
Published: June 2021

Chlorine (Cl2) is a toxic oxidative gas that can cause acute lung injury (ALI) and death when inhaled at high concentrations for extended periods of time. Used in the production of pharmaceuticals, Cl2 exposure can occur in industrial or transportation accidents, which are common enough to pose a serious health risk. Cl2 insult results in coagulatory dysfunction, inflammatory damage and increased lung permeability. Thus we hypothesized that delivery of aerosolized heparin, which is an anticoagulant that decreases fibrin deposition and does not cause significant systemic bleeding when administered intranasally, may decrease lung injury. C57BL/6 mice were exposed to 400ppm Cl2 for 30min in environmental chambers and returned to room air. Immediately following Cl2 exposure, they were connected to a nebulizer and breathed heparin or vehicle for 20 min. At 1hr post aerosol, blood and bronchoalveolar lavage fluid (BALF) were taken for native rotational thromboelastometry (NATEM) and thrombin antithrombin (TAT) formation measurements (an index of clotting). At 6hrs post aerosol, BALF from a second group of mice was taken for measurements of total protein (an index of increased blood‐gas permeability) and white blood cell (WBC) numbers (an index of inflammation). Mice that received heparin had significantly faster coagulatory times and significantly lower levels of total protein and number of inflammatory cells in the BALF. These results suggest that heparin mitigates Cl2 induced lung damage, especially in the reduction of lung permeability, WBC inflammatory responses and post injury hypocoagulation.Grant Funding Source: Supported by: NIEHS grants 5U54ES017218, 5U01ES015676 and a European Respiratory Society Fellowship
Neuron‐specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD knockout mice (1153.3)
Authors: Sakellariou Giorgos , Davis Carol , Shi Yun , Ivannikov Maxim , Zhang Yiqiang , Giakoumaki Ifigeneia , Vasilaki Aphrodite , Macleod Gregory , Richardson Arlan , Van Remmen Holly , Jackson Malcolm , McArdle Anne , Brooks Susan 
Published: June 2021

Deletion of CuZnSOD in Sod1‐/‐ mice leads to accelerated loss of muscle mass and force during aging. To determine the role of motor neurons in the muscle declines, we generated a transgenic Sod1‐/‐ mouse in which CuZnSOD was expressed under control of a synapsin 1 promoter (SynTgSod1‐/‐ mice). These “rescue” mice expressed CuZnSOD in brain, spinal cord, and peripheral nerves, but not other tissues. Sciatic nerve CuZnSOD content in SynTgSod1‐/‐ mice was ~20% that of control mice, but no reduction in muscle mass or maximum isometric force was observed for the rescue mice compared with controls at 15 months, whereas muscles of age‐matched Sod1‐/‐ mice displayed 30‐35% reductions in mass and force. Increased oxidative damage and adaptations in stress responses observed in muscles of Sod1‐/‐ mice were absent in SynTgSod1‐/‐ mice and accelerated degeneration of neuromuscular junction (NMJ) structure occurred in Sod1‐/‐ mice but not SynTgSod1‐/‐ mice. Our data demonstrate that CuZnSOD expression in neurons is sufficient to preserve NMJ and skeletal muscle structure and function in Sod1‐/‐ mice and suggest that redox homeostasis in motor neurons plays a key role in the initiation of sarcopenia during aging.Grant Funding Source: Supported by the US National Institute on Aging (Grant No: AG‐020591)
Capsaicin‐induced cardioprotection is driven by its hypothermic effect (1154.1)
Authors: Dow Joan , Simkhovich Boris , Hale Sharon , Kay Gregory , Kloner Robert 
Published: June 2021

Objective. We hypothesized that cardioprotective properties of topical capsaicin (CAP) application are related to its hypothermic effect.Methods. Anesthetized rats received CAP cream or vehicle (VCL) applied 15‐30 minutes before a 30‐minute coronary artery occlusion followed by 2‐hour reperfusion. At the end of the protocol, hearts were excised and the area at risk (AR), area of necrosis (AN) and infarct size (AN/AR) were measured. In additional set of animals, hearts were excised at the end of CAP/VCL application, and used for Western Blot assay of p‐Akt and p‐Erk1/2.Results. CAP cream produced a rapid decrease in pre‐occlusion core temperature, ranging from 0.22 to 1.78°C, with a median reduction of 0.97°C. In a CAP subgroup with a temperature decrease of > 0.97°C, AN/AR was decreased by 31% (from 56±4% in the VCL group to 38±4% in the CAP group, p<0.05). In the CAP subgroup with temperature decrease < 0.97°C no difference in the infarct size was observed. CAP induced an increase in p‐Akt and p‐Erk1/2. Phosphorylation of downstream p70S6 was unaffected. Levels of p‐Akt‐ and p‐Erk1/2 did not correlate with temperature at pre‐occlusion.Conclusion. In the current study we for the first time demonstrated that cardioprotective effect of capsaicin might be related to mild hypothermia, caused by its topical application. Salvage kinase pathway appears not to be critical for the cardioprotective effects of capsaicin.
Mdivi‐1 mitigates cardiac dysfunction by attenuating mitophagy in diabetes (1155.3)
Authors: Mishra Paras Kumar , Nandi Shyam , Chavali Vishalakshi 
Published: June 2021

Although Mdivi‐1 ameliorates heart failure by inhibiting autophagy, the mechanism of Mdivi‐1 mediated mitigation of cardiac dysfunction in diabetes is unclear. We hypothesize that Mdivi‐1 improves LV function by mitigating mitophagy in diabetic hearts. The three major sequencial steps required for mitophagy are: smaller size of mitochondria (by excessive fission), decrease in ΔΨm (for initiation of mitophagy) and increase in autophagophore formation (induction of beclin‐1 that initiates autophagy pathway). To investigate cardiac mitophagy, we measured dynamin like receptor‐1 (drp1, fission protein), JC1 (for ΔΨm) and beclin1, Atg3, LC3B (for autophagosome) by RT‐qPCR, Immunoblotting(IB) and immunofluoresence (IF) in male C57BL/6J and Ins2+/‐ (spontaneous, chronic,T1D) mice treated with Mdivi‐1 (50mg/kg, ip./day for 7days). The cardiac dysfunction was evaluated by M‐mode echocardiography. For in vitro study, HL1 cardiomyocytes were treated with low (5mM, LG) and high (25mM, HG) dose of glucose, and Mdivi‐1 (50µmol/L for 40 min). In Ins2+/‐ mice, Mdivi‐1 treatment decreases drp1 (IF,3.8±0.6 folds), beclin1 (IB,2.2±0.3 fold), Atg3 (IB,2.05±0.1 fold) and LC3b (IB,3.4±0.2 fold) but increases both %FS (32.6 ± 2.8 vs 42.6 ± 2.9) and %EF (60.7±4.3 vs 79.6±2.9). Mdivi‐1 did not have effect on blood glucose levels. In HL1 cardiomyocytes, Mdivi‐1 significantly decreases hypopolarized (mitophagy prone) mitochondria (JC1 staining green, IF, 2.3±0.1 fold) that prevents initiation of mitophagy in diabetic cardiomyocytes. This is a novel mechanism of Mdivi‐1 mediated mitigation of mitophagy and amelioration of diabetic cardiomyopathy.Grant Funding Source: NIH, HL113281 and HL116205
Peripheral vascular function in heart failure patients with preserved ejection fraction (1156.4)
Authors: Barrett‐O'Keefe Zachary , Lee Joshua , Ryan John , Nativi Jose , Richardson Russell , Wray D. 
Published: June 2021

While peripheral vascular dysfunction is well‐described in heart failure patients with reduced ejection fraction, disease‐related changes in vascular function in heart failure patients with preserved ejection fraction (HFpEF) remains unclear. Thus, in six HFpEF patients (73 ± 4 yrs) and six healthy controls matched for age (74 ± 4 yrs), sex, and brachial artery (BA) diameter, ultrasound Doppler was utilized to determine BA flow‐mediated vasodilation (FMD) and reactive hyperemia (RH) following 5 minutes of suprasystolic cuff occlusion. BA FMD was lower in HFpEF patients (3.9 ± 0.9 %) compared to controls (6.0 ± 1.0 %). Likewise, the RH response, calculated as the cumulative BA blood flow (area under the curve), was reduced by ~50% in patients with HFpEF compared to controls (385 ± 56 vs. 698 ± 104 ml, HFpEF vs. controls). These results indicate a clear impairment in peripheral vascular function in patients with HFpEF beyond that observed with healthy aging, providing new insight into the pathophysiology of this understudied disease.Grant Funding Source: Supported by NIH PO1 HL‐091830, VA RR&D E6910R, and AHA 0835209N.
Enhanced vasoconstrictor sensitivity to exercise pressor reflex engagement in peripheral arterial disease (1156.7)
Authors: Gao Zhaohui , Blaha Cheryl , Cauffman Aimee , Brandt Kristen , Reed Amy , Sinoway Lawrence , Leuenberger Urs 
Published: June 2021

Exercise is associated with a rise in heart rate, blood pressure (BP) and blood flow to active muscle mediated by the exercise pressor reflex and regional release of vasodilators. In peripheral arterial disease (PAD) the exercise pressor reflex is enhanced. To assess the functional impact of the exercise pressor reflex, we determined BP and mean blood velocity (MBV, Doppler) in the popliteal artery and calculated vascular conductance (VC, MBV/mean BP) in the exercising and contralateral legs during graded rhythmic plantar flexion in 7 patients with PAD (age 67±2 yrs, ankle‐brachial‐index 0.6±0.1 in the ischemic leg) and in 5 controls. At peak exercise (2.0 kg, 1 Hz), the pressor effect was greatest in PAD when exercise was performed with the ischemic leg, and lowest in the controls. In controls, exercise did not affect VC in the contralateral inactive leg (P=NS). Similarly, in PAD, exercise in the ischemic leg did not affect VC in the opposite inactive leg (P=NS). In contrast, during exercise with the non‐ischemic leg, VC in the contralateral ischemic leg decreased by 24±10% (P<0.05). Thus, activation of the exercise pressor reflex resulted in vasoconstriction in the inactive but diseased leg. This suggests that despite upregulation of peripheral vasodilator factors, the vasculature of the ischemic leg is exquisitely sensitive to reflex vasoconstriction.Grant Funding Source: Supported by P01 HL096570 and UL1 TR000127
Renal responses to severe haemorrhage in conscious lambs: role of kappa opioid receptors (1157.1)
Authors: Smith Francine , Samhan Mohamed , Qi Wei 
Published: June 2021

In previous studies, we showed that activation of kappa opioid receptors (KORs) alters cardiorenal function in conscious newborn lambs. The endogenous ligand for KORs, Dynorphin, is increased in response to blood loss, although any role for KORs in the renal responses to haemorrhage in the newborn is not known. Therefore, in conscious newborn lambs (N=7, aged 7 to 9 days), various parameters of glomerular and tubular function were measured for 30 min before (Control) and 120 min after 30% haemorrhage after pretreatment with vehicle (experiment one) or the selective KOR antagonist, GNTI (experiment two). After vehicle, glomerular filtration rate decreased 30 min after haemorrhage from 0.24±0.08 to 0.14±0.05 mL/min/g and remained at 0.19±0.08 mL/min/g at 120 min. Renal plasma flow decreased by 30 min from 1.5±0.5 to 0.7±0.2 and then increased to 1.1±0.4 mL/min/g after 120 min. Urinary flow rates and electrolyte clearances also decreased after haemorrhage. These renal responses were not altered by pretreatment with GNTI. In contrast, after vehicle, free water clearance decreased from ‐0.6±1.8 to ‐1.8±1.2 μL/min/g 30 min after haemorrhage, but increased after pretreatment with GNTI from ‐1.1±1.0 to 1.3±0.6 μL/min/g. Therefore, in the newborn period, KORs appear to regulate tubular water reabsorption but are not involved in other tubular or glomerular responses to severe blood loss.Grant Funding Source: Supported by the CIHR.
Pulmonary permeability after hemorrhage and resuscitation in the obese Zucker rat (1157.2)
Authors: Clemmer John , Xiang Lusha , Lu Silu , Mittwede Peter , Hester Robert 
Published: June 2021

Acute lung injury is a major cause of mortality and is the most frequent and earliest outcome seen in obese trauma patients. Moreover, obese patients are associated with increased morbidity and mortality after hemorrhage and resuscitation (H/R), however, the mechanisms are unclear. We hypothesized that, as compared to lean Zucker rats (LZ), obese Zucker rats (OZ) have increased lung vulnerability to H/R. Conscious animals were hemorrhaged 35% of their total blood volume and resuscitated with an equivalent volume of Ringer’s lactate. Three hours after H/R, OZ had an increased bronchoalvolar lavage to plasma protein ratio (0.12 ± 0.03) as compared to LZ (0.05 ± 0.01) suggesting increased permeability in OZ. This was associated with a greater increase in lung NADPH oxidase activity in OZ as compared to LZ. In order to consider superoxide as a factor that could play a role in lung permeability, isolated lung experiments were performed to measure basal lung capillary permeability (Kf) with or without the superoxide donor, PMS. Acute PMS treatment increased baseline lung Kf in LZ from 11 ± 2 to 53 ± 9 ml/mmHg/g/min and in OZ from 21 ± 3 to 98 ± 17 ml/mmHg/g/min, with a significantly greater increase in OZ. Basal lung Kf was significantly greater in OZ compared to LZ. These data suggest that obesity may increase vulnerability to H/R due to increased basal lung Kf and/or exacerbated production or sensitivity to lung superoxide.Grant Funding Source: Supported by AHA‐12SDG12050525, NIH HL‐51971,HL‐89581, and T32 HL‐105324
Serum pregnancy‐associated plasma protein‐A levels in a cohort with cardiovascular disease (1158.2)
Authors: Gerthoffer William , Hellmich Alexandria , Aragon Ileana , Massey Clara 
Published: June 2021

Patients with acute coronary syndrome (ACS) who have high serum levels of pregnancy‐associated plasma protein‐A (PAPP‐A) are at increased risk of cardiac events. PAPP‐A levels have been reported to indicate elevated risk in ACS patients who were troponin I‐negative. The long range goal is to assess changes in PAPP‐A levels in a longitudinal study of subjects diagnosed with cardiovascular disease to further test the validity of serum levels of PAPP‐A as a predictor of adverse cardiovascular events. Initial serum levels of PAPP‐A were measured in a cohort of 243 subjects to establish the reference range for the cohort. Serum PAPP‐A levels were measured using a commercial sandwich type immunoassay using dual wavelength colorimetric detection. Serum PAPP‐A levels ranged from 0.43 to 4.2 ng/ml with geometric mean and 95% CI of 0.95 (0.87 ‐ 0.97) ng/ml. A correction factor of 2.7 international units/ng PAPP‐A was used to calculate the reference range in mIU/L (0.4 ‐ 11). Median values of serum PAPP‐A did not vary significantly with gender or race, nor were there significant correlations with increasing age, mean arterial blood pressure or total cholesterol. Although PAPP‐A levels did not correlate with these known cardiovascular risk factors in this cross‐sectional analysis the data do provide a reference range of the cohort that is similar to published reports of PAPP‐A levels in subjects at other clinical centers.Grant Funding Source: Supported by grant P20MD0002314‐06 from NIMHD
Increased Rho‐kinase activity and reactive oxygen species contribute to the enhanced vasoconstrictor effects of angiotensin II in aortic rings from sepsis‐surviving rats (1158.3)
Authors: de Souza Priscila , da Silva Luisa , Scheschowitsch Karin , Guarido Karla , Werner M. Fernanda , Assreuy Jamil , Marques M. Consuelo , da Silva‐Santos José Eduardo 
Published: June 2021

We hypothesized that changes in vascular reactivity contribute to the high mortality rate among patients discharged after severe sepsis/septic shock. Male Wistar rats were subjected to cecal ligation and puncture to induce sepsis (mortality around 30%) and aortic rings from survived animals were tested at 30 or 60 days after (S30 and S60 groups). The effects of KCl, phenylephrine, angiotensin I, CaCl2, acetylcholine and sodium nitroprusside did not change, but angiotensin II (AII)‐induced constriction was increased by 80% in aortic rings from S60. The removal of endothelium, incubation with L‐NAME (inhibitor of nitric oxide synthase), or inhibition of Rho‐kinase by Y‐27632 did not change the effects of AII in these vessels, which showed increased protein levels of both RhoA and ROCK II. Incubation with apocynin (NADPH oxidase inhibitor), SOD, or tempol (O2‐ scavenger) did not change the effect of AII in control rings, but avoided the increased reactivity to AII in vessels from S60 rats. The endogenous activity of SOD was decreased by 45 ± 3%, while the generation of LOOH and GSH were increased by 41 ± 12% and 98 ± 3.9% in the aorta of S60 rats. A selective fluorescent probe revealed an increased ROS generation (up to 30%) in vessels from S60 rats after stimulation with AII. In conclusion, aortic rings from sepsis‐surviving rats display increased reactivity to AII, which involves augmented activity of ROCK and oxidative stress.Grant Funding Source: Supported by CAPES, CNPq, FAPESC
Potential role of AT2R on the cardiac mitochondrial metabolism in the hyperthyroidism condition (1159.8)
Authors: Silva Ivson , Lima Vanessa , Souza dos Santos Robson , Ferreira Julio Cesar , Barreto‐Chaves Maria Luiza 
Published: June 2021

Thyroid hormone (TH) is known to influence the mitochondrial metabolism. Recently, it has been proposed that the intracellular renin angiotensin system (iRAS) seems to be activated by high levels of (TH). However, the contribution of AT2R in the regulation of cardiac mitochondrial metabolism or the possible effect of TH on this event was not elucidated yet. We investigated the potential role of AT2R on the cardiac mitochondrial metabolism and the possible influence of the hyperthyroidism on this process. Four groups of mice were used: wild‐type (WT), WT treated with TH (0.7 µg/Kg BW/day, i.p.) for 14 days, knockout (KO AT2R‐/y) mice and KO AT2R‐/y mice treated with TH. Cardiac mitochondria were isolated and the oxygen consumption was assessed by oxymetry. The H2O2 production was also analyzed. The determination of maximal oxygen uptake was determined by indirect calorimetry open circuit. Data were analyzed by two‐way ANOVA. The KO mice presented a reduction in all parameters analyzed: states 2, 3, 4 and respiratory control ratio in relation to control. The TH‐treated WT did not present changes on H2O2 production. However, H2O2 production was higher on KO mice treated with TH. Indeed, the calorimetry showed a decrease (17%) on basal metabolic rate of on KO mice. Taken together, our data show that AT2R may be involved in the control of cardiac mitochondrial metabolism and influence the effect of hyperthyroidism in this parameter.Grant Funding Source: Supported by CNPq/CAPES and FAPESP
Brown adipose tissue thermal activity is influenced by season in healthy children (1160.1)
Authors: Astle Val , Zhang Taouri , Robinson Lindsay , Law James , Townsend Ellen , Symonds Michael , Pitchford Nicola , Budge Helen 
Published: June 2021

Brown adipose tissue (BAT), present in the supraclavicular region of humans, can be activated by cold stimuli, and even small quantities could result in a large increase in energy expenditure. PET‐CT studies have identified more glucose uptake into BAT in winter months. This study was conducted to determine if seasonality had an effect on thermal activity of BAT. Infrared thermography, a technique previously established for this use in children, was used to detect the skin temperature overlying BAT depots in the supraclavicular region. Skin temperatures were recorded in the steady state and 5 minutes after a cool stimulus (hand placed into water at 20°C). The study was conducted at schools in age‐matched children aged 8‐11 years in the Summer (n=27) and in the Winter (n=25). The interoperator coefficient of variation (CV) (mean 4.11% (range 0.98‐9.04%) and intraobserver CV (mean 0.18% (range 0.01‐0.38%) were within acceptable limits. In line with our previous published studies, we found that BMI had a significant negative effect on baseline temperature (p<0.001). In addition, baseline skin temperature overlying BAT in the supraclavicular region was significantly greater in Winter (p=0.017, R2=0.31) than Summer independent of BMI, gender, age and room temperature. Future studies of brown adipose tissue activity during daily activities are required to determine possible factors which may be utilised to increase metabolic activity and, therefore, decrease white fat deposition.Grant Funding Source: Action Research