Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways

Tesfai, A. et al. (2017) Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways. PLoS ONE, 12(8), e0183025. (doi: 10.1371/journal.pone.0183025) (PMID:28813479) (PMCID:PMC5557592)

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Abstract

Rationale: Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known. Objective: Our objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity. Methods and measurements: 34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24–72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay. Main results: Of all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis. Conclusions: In early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Leiper, Professor James
Authors: Tesfai, A., MacCallum, N., Kirkby, N. S., Gashaw, H., Gray, N., Want, E., Quinlan, G. J., Mumby, S., Leiper, J. M., Paul-Clark, M., Ahmetaj-Shala, B., and Mitchell, J. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2017 Tesfai et al.
First Published:First published in PLoS ONE 12(8):e0183025
Publisher Policy:Reproduced under a Creative Commons License

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