Red blood cells in hemorrhagic shock: a critical role for glutaminolysis in fueling alanine transamination in rats

Reisz, Julie A.; Slaughter, Anne; Culp‐Hill, Rachel; Moore, Ernest E.; Silliman, Christopher C.; Fragoso, Miguel; Peltz, Erik D.; Hansen, Kirk C.; Banerjee, Anirban; D’Alessandro, Angelo

doi:10.1182/bloodadvances.2017007187

Cited by 24 publications

(29 citation statements)

References 55 publications

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“…Similarly, RBC levels of some carboxylic acids (e.g., malate, 2-hydroxyglutarate) were higher in humans, whereas others (e.g., citrate, α-ketoglutarate, succinate, oxaloacetate, itaconate) were higher in RM ( Figure 5B ), suggesting species-specific differences in transamination reactions (e.g., those dependent on the activity of alanine and aspartate aminotransferases) or carboxylic acid metabolism via cytosolic isoforms of Krebs cycle enzymes, all of which are active in mature RBC. 34 , 36 – 38 …”

Section: Resultsmentioning

confidence: 99%

“…35 Consistent with dysregulation of purine oxidation and salvage, species-specific changes in aspartate (higher in RMs) and fumarate (higher in humans) levels were noted, suggesting a decreased rate of salvage reactions in RM RBCs (Figure 5B). Similarly, RBC levels of some carboxylic acids (e.g., malate, 2-hydroxyglutarate) were higher in humans, whereas others (e.g., citrate, alphaketoglutarate, succinate, oxaloacetate, itaconate) were higher in RMs (Figure 5B), suggesting species-specific differences in transamination reactions (e.g., those dependent on the activity of alanine and aspartate aminotransferases) or carboxylic acid metabolism via cytosolic isoforms of Krebs cycle enzymes, all of which are active in mature RBCs 34,[36][37][38] .…”

Section: Species-specific Differences In Metabolic Phenotypes Of Stormentioning

confidence: 99%

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Red blood cell metabolism in Rhesus macaques and humans: comparative biology of blood storage

et al. 2019

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247/250Abstract Macaques are emerging as a critical animal model in transfusion medicine, owing to their evolutionary similarity to humans and perceived utility in discovery and translational science.However, little is known about the metabolism of rhesus macaque red blood cells and how they compare to human RBCs under standard blood banking conditions. Metabolomics and lipidomics analyses, and tracing experiments with [1,2,3-13 C 3 ]glucose, were performed using fresh and stored red cells (sampled weekly until storage day 42) obtained from rhesus macaques (n=20) and healthy human volunteers (n=21). These results were further validated with targeted quantification against stable isotope-labeled internal standards. Metabolomics analyses demonstrated inter-species differences in red cell metabolism independent of refrigerated storage. Although similar trends were observed throughout storage for several metabolic pathways, species-and sex-specific differences were also observed. Most notable were differences in glutathione and sulfur metabolites, purine and lipid oxidation metabolites, acylcarnitines, fatty acyl composition of several classes of lipids (including phosphatidylserines), glyoxylate pathway intermediates, and arginine and carboxylic acid metabolites. Species-specific dietary and environmental compounds were also detected. Overall, the results suggest an increased basal and refrigerator-storage-induced propensity for oxidant stress and lipid remodeling in rhesus macaque, as compared to human, red cells. The overlap between rhesus macaque and human red cell metabolic phenotypes suggests the potential utility of a translational model for simple red blood cell transfusions, though inter-species storage-dependent differences need to be considered when modeling complex disease states, such as transfusion in trauma/hemorrhagic shock models.

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Section: Resultsmentioning

confidence: 99%

Section: Species-specific Differences In Metabolic Phenotypes Of Stormentioning

confidence: 99%

Red blood cell metabolism in Rhesus macaques and humans: comparative biology of blood storage

et al. 2019

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“…Fresh baboon RBCs also have a similar lifespan to humans (∼100 days) (Valeri et al, 2002), and hydrogen peroxide-damaged baboon RBCs have increased levels of spectrin-hemoglobin complexes facilitating more rapid removal from circulation (McKenney et al, 1990). Further, RBCs in both humans and baboons respond to altitude (D'Alessandro et al, 2016) or hemorrhagic hypoxia (Reisz et al, 2017) by promoting synthesis of 2,3-diphosphoglycerate, thereby enhancing hemoglobin transition state responsiveness to pH and carbon dioxide; this process promotes hemoglobin's T state conformation (right shift of the hemoglobin oxygen-dissociation curve), oxygen off-loading, and restoration of tissue oxygen homeostasis (Herman et al, 1971).…”

Section: Introductionmentioning

confidence: 99%

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

et al. 2020

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As part of the ZOOMICS project, we set out to investigate common and diverging metabolic traits in the blood metabolome across various species by taking advantage of recent developments in high-throughput metabolomics. Here we provide the first comparative metabolomics analysis of fresh and stored human (n = 21, 10 males, 11 females), olive baboon (n = 20), and rhesus macaque (n = 20) red blood cells at baseline and upon 42 days of storage under blood bank conditions. The results indicated similarities and differences across species, which ultimately resulted in a differential propensity to undergo morphological alterations and lyse as a function of the duration of refrigerated storage. Focusing on purine oxidation, carboxylic acid, fatty acid, and arginine metabolism further highlighted species-specific metabolic wiring. For example, through a combination of steady state measurements and 13 C 6 15 N 4-arginine tracing experiments, we report an increase in arginine catabolism into ornithine in humans, suggestive of species-specific arginase 1 activity and nitric oxide synthesis-an observation that may impact the translatability of cardiovascular disease studies carried out in non-human primates (NHPs). Finally, we correlated metabolic measurements to storage-induced morphological alterations via scanning electron microscopy and hemolysis, which were significantly lower in human red cells compared to both NHPs.

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“…RBC metabolism thus mirrors systemic metabolic homeostasis and its pathological derangements beyond traditional RBC-specific pathologies, such as sickle cell disease 5 (eg, HbA1c and diabetes). 1 More recently, it has been suggested that RBC metabolism might mirror acute (eg, hemorrhagic shock 6 or physical activity 7 ) and/or chronic metabolic aberrations, such as in aging 4 and inflammation. 7 Trisomy 21 (T21) is the etiological factor of Down syndrome (DS), the most common chromosomal abnormality in the human population, occurring in 1 in ;700 live births in the United States.…”

Section: Introductionmentioning

confidence: 99%

Red blood cell metabolism in Down syndrome: hints on metabolic derangements in aging

et al. 2017

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Red blood cells in hemorrhagic shock: a critical role for glutaminolysis in fueling alanine transamination in rats

Abstract: Key Points• In vivo tracing of 13 C 15 N-glutamine reveals that glutaminolysis is an essential contributor to RBC metabolism following HS.• Inhibition of glutaminolysis impairs transamination reactions and GSH synthesis, promoting early mortality in hemorrhaged rats.

Cited by 24 publications

References 55 publications

Red blood cell metabolism in Rhesus macaques and humans: comparative biology of blood storage

Red blood cell metabolism in Rhesus macaques and humans: comparative biology of blood storage

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

Red blood cell metabolism in Down syndrome: hints on metabolic derangements in aging

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