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Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis.

Ivanisevic J, Elias D, Deguchi H, Averell PM, Kurczy M, Johnson CH, Tautenhahn R, Zhu Z, Watrous J, Jain M, Griffin J, Patti GJ, Siuzdak G - Sci Rep (2015)

Bottom Line: Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome.While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids.This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology.

View Article: PubMed Central - PubMed

Affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology.

No MeSH data available.


Metabolites that varied significantly after the blood circulation across the muscle tissue, as validated by targeted analysis.Paired plots show the abundances of each metabolite in arterial and venous plasma of each individual. Significance level of Wilcoxon test is indicated by the number of stars.
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f5: Metabolites that varied significantly after the blood circulation across the muscle tissue, as validated by targeted analysis.Paired plots show the abundances of each metabolite in arterial and venous plasma of each individual. Significance level of Wilcoxon test is indicated by the number of stars.

Mentions: Changes in arterial vs. venous levels were determined for 36 endogenous metabolites using targeted multiple reaction monitoring. The summary of quantified metabolites with the associated arteriovenous fold changes (arterial/venous (A/V) or venous/arterial (V/A) ratios) and levels of significance is given in Fig. 4. Direction of the fold change implies either the positive arteriovenous balance reflecting the metabolite uptake by the organ or the negative arteriovenous balance reflecting the metabolite release by the organ. Metabolite levels (i.e. dynamic range) in both, arterial and venous plasma, varied significantly from one individual to another, up to 10 times, depending on the metabolite of interest. Lactate, was measured together with glucose, as the most abundant among the quantified metabolites (1453 ± 109.4 μM in arterial and 1728 ± 180.1 μM in venous plasma, Figure S2), followed by amino acids (glutamine, glutamate) also detected in high concentrations (≥100 μM) in arterial and venous plasma (Figure S2). Levels of ten different amino and non-amino organic acids were observed to change significantly between arterial and venous plasma, following the passage through the human peripheral tissue (skeletal muscle). Although subtle, the arteriovenous fold changes (from V/A = 1.09 fold for sialic acid to A/V = 3.02 fold for glutamate, Fig. 4, Figure S1) were consistent across the majority of analyzed subjects (Fig. 5). Glutamate showed the highest uptake pattern (or the highest positive arteriovenous balance (3.02 ± 0.32 fold lower in venous plasma, p < 0.0001, Figs 3 and 4) while lactate (1.31 ± 0.06 fold higher in venous plasma, p < 0.0001, Figs 3 and 4) and succinate (1.56 ± 0.09 fold higher in venous plasma, p < 0.0001, Figure S1) displayed the most significant release pattern across human forearm tissue (Fig. 4). In addition to glutamate; aspartate and serine displayed consistent uptake patterns as well, with significantly decreased levels in venous vs. arterial plasma while alanine, glutamine and phenylalanine together with lactate, succinate, malate and sialic acid exhibited a consistent release pattern with significantly increased levels in venous vs. arterial plasma (Figs 4 and 5). The majority of other targeted amino acids exhibited higher content in venous plasma (qualified as negative arteriovenous balance, e.g. tryptophan, cystine, arginine, aspargine, glycine, histidine, ornithine, Fig. 4), although the difference was not statistically significant. The exceptions were branched amino acids (BAA: leucine, isoleucine and valine), which displayed a positive arteriovenous balance (like previously mentioned glutamate, aspartate and serine) although the statistical significance for BAA was not reached (Fig. 4).


Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis.

Ivanisevic J, Elias D, Deguchi H, Averell PM, Kurczy M, Johnson CH, Tautenhahn R, Zhu Z, Watrous J, Jain M, Griffin J, Patti GJ, Siuzdak G - Sci Rep (2015)

Metabolites that varied significantly after the blood circulation across the muscle tissue, as validated by targeted analysis.Paired plots show the abundances of each metabolite in arterial and venous plasma of each individual. Significance level of Wilcoxon test is indicated by the number of stars.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525490&req=5

f5: Metabolites that varied significantly after the blood circulation across the muscle tissue, as validated by targeted analysis.Paired plots show the abundances of each metabolite in arterial and venous plasma of each individual. Significance level of Wilcoxon test is indicated by the number of stars.
Mentions: Changes in arterial vs. venous levels were determined for 36 endogenous metabolites using targeted multiple reaction monitoring. The summary of quantified metabolites with the associated arteriovenous fold changes (arterial/venous (A/V) or venous/arterial (V/A) ratios) and levels of significance is given in Fig. 4. Direction of the fold change implies either the positive arteriovenous balance reflecting the metabolite uptake by the organ or the negative arteriovenous balance reflecting the metabolite release by the organ. Metabolite levels (i.e. dynamic range) in both, arterial and venous plasma, varied significantly from one individual to another, up to 10 times, depending on the metabolite of interest. Lactate, was measured together with glucose, as the most abundant among the quantified metabolites (1453 ± 109.4 μM in arterial and 1728 ± 180.1 μM in venous plasma, Figure S2), followed by amino acids (glutamine, glutamate) also detected in high concentrations (≥100 μM) in arterial and venous plasma (Figure S2). Levels of ten different amino and non-amino organic acids were observed to change significantly between arterial and venous plasma, following the passage through the human peripheral tissue (skeletal muscle). Although subtle, the arteriovenous fold changes (from V/A = 1.09 fold for sialic acid to A/V = 3.02 fold for glutamate, Fig. 4, Figure S1) were consistent across the majority of analyzed subjects (Fig. 5). Glutamate showed the highest uptake pattern (or the highest positive arteriovenous balance (3.02 ± 0.32 fold lower in venous plasma, p < 0.0001, Figs 3 and 4) while lactate (1.31 ± 0.06 fold higher in venous plasma, p < 0.0001, Figs 3 and 4) and succinate (1.56 ± 0.09 fold higher in venous plasma, p < 0.0001, Figure S1) displayed the most significant release pattern across human forearm tissue (Fig. 4). In addition to glutamate; aspartate and serine displayed consistent uptake patterns as well, with significantly decreased levels in venous vs. arterial plasma while alanine, glutamine and phenylalanine together with lactate, succinate, malate and sialic acid exhibited a consistent release pattern with significantly increased levels in venous vs. arterial plasma (Figs 4 and 5). The majority of other targeted amino acids exhibited higher content in venous plasma (qualified as negative arteriovenous balance, e.g. tryptophan, cystine, arginine, aspargine, glycine, histidine, ornithine, Fig. 4), although the difference was not statistically significant. The exceptions were branched amino acids (BAA: leucine, isoleucine and valine), which displayed a positive arteriovenous balance (like previously mentioned glutamate, aspartate and serine) although the statistical significance for BAA was not reached (Fig. 4).

Bottom Line: Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome.While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids.This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology.

View Article: PubMed Central - PubMed

Affiliation: Center for Metabolomics and Mass Spectrometry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology.

No MeSH data available.