An O-GlcNAcylomic Approach Reveals ACLY as a Potential Target in Sepsis in the Young Rat.

Manon Denis,Bertrand Rozec,Anaïs Maillard,Antoine Persello,Didier Vertommen,Thomas Pelé,Charlotte Betus,Thomas Dupas,Angélique Erraud,Benjamin Lauzier,Jérôme Montnach,Jacques Lebreton,Arnaud Tessier,Michel De Waard,Luc Bertrand,Justine Dontaine,Laurent Bultot,M Riviere ,J Dhot ,Édith Bigot-Corbel ,Aurélia Leroux

doi:10.3390/ijms22179236

Abstract

Sepsis in the young population, which is particularly at risk, is rarely studied. O-GlcNAcylation is a post-translational modification involved in cell survival, stress response and metabolic regulation. O-GlcNAc stimulation is beneficial in adult septic rats. This modification is physiologically higher in the young rat, potentially limiting the therapeutic potential of O-GlcNAc stimulation in young septic rats. The aim is to evaluate whether O-GlcNAc stimulation can improve sepsis outcome in young rats. Endotoxemic challenge was induced in 28-day-old rats by lipopolysaccharide injection (E. Coli O111:B4, 20 mg·kg−1) and compared to control rats (NaCl 0.9%). One hour after lipopolysaccharide injection, rats were randomly assigned to no therapy, fluidotherapy (NaCl 0.9%, 10 mL·kg−1) ± NButGT (10 mg·kg−1) to increase O-GlcNAcylation levels. Physiological parameters and plasmatic markers were evaluated 2h later. Finally, untargeted mass spectrometry was performed to map cardiac O-GlcNAcylated proteins. Lipopolysaccharide injection induced shock with a decrease in mean arterial pressure and alteration of biological parameters (p < 0.05). NButGT, contrary to fluidotherapy, was associated with an improvement of arterial pressure (p < 0.05). ATP citrate lyase was identified among the O-GlcNAcylated proteins. In conclusion, O-GlcNAc stimulation improves outcomes in young septic rats. Interestingly, identified O-GlcNAcylated proteins are mainly involved in cellular metabolism.

Highlights

Sepsis is a dysregulated response of the host to an infectious pathogen whose response varies according to the pathogen and host
We have previously demonstrated that O-GlcNAcylation varies throughout aging [19]
We have demonstrated that NButGT treatment leading to increasing O-GlcNAcylation levels (~1.5 fold) and restoring SBP and MAP is effective in young rats despite physiologically higher O-GlcNAcylation levels

Summary

Introduction

Sepsis is a dysregulated response of the host to an infectious pathogen whose response varies according to the pathogen and host. It is the result of a systemic inflammatory response syndrome (SIRS) following an infection [1,2,3,4]. Sepsis is an important but potentially preventable cause of pediatric death worldwide, with a mortality range from 4% to 50%. It causes 28% of mild disability in Europe [8]. Appropriate resuscitation and management are the key to optimizing outcomes for children with sepsis [9]

Methods

Results

Discussion

Conclusion