O-GlcNAc stimulation, a new hope for children in sepsis?

Abstract

O-GlcNAc stimulation, a post-translational modification, at the early phase of septic shock has been shown to be a potent new therapeutic strategy for adult. Young population is particularly at risk of septic shock but is rarely studied. O-GlcNAc level are regulated by cell metabolism through the hexosamine biosynthetic pathway (HBP). Metabolism evolves throughout development with a potential impact on O-GlcNAc level, hence responses to O-GlcNAc stimulation could be different in young. To evaluate O-GlcNAc level from birth to adulthood in heart and evaluate if an increase in protein O-GlcNAcylation could improve sepsis outcomes in young. Hearts were harvested from Wistar rats at day 0 - D0 (newborn), D12, D28 (before/after weaning) and D84 (adulthood) to evaluate O-GlcNAc, GFAT (the rate limiting enzyme of HBP), OGA (O-GlcNAcase) and OGT (O-GlcNAc transferase) levels. To induce an endotoxemic shock, D28 rats received an I.V. LPS injection (O111:B4-20 mg.kg-1) and 1 h after, fluidotherapy (LPS + R) ± NButGT (NButGT-10 mg.kg-1). 2 h later, physiological function (arterial blood pressure, heart and respiratory rate) and plasmatic markers of severity were measured. O-GlcNAc level decreased from D0 to D84 (6 fold) along with GFAT (30 fold) and OGT (5 fold) while the OGA is absent at D0 and increase progressively. LPS induced an alteration of physiological parameters (mean arterial pressure (MAP): CTRL: 67,2 ± 1,9; LPS: 50,7 ± 2,1 mmHg; P < 0,05), biological parameters (lactates: CTRL: 3,92 ± 0,26; LPS: 6,42 ± 0,45 mmol.l-1; troponin: CTRL: 19,7 ± 4,0; LPS: 45,4 ± 11,4 ng.l-1; P < 0,05) and in adapted-PRISM Score. NButGT restored MAP (NButGT: 72.2 ± 4.0 mmHg; P < 0.05) and adapted-PRISM Score (NButGT: 9.7 ± 0.6; P < 0.05). Despite higher O-GlcNAc level in young population and that high O-GlcNAc level are commonly deleterious, an acute O-GlcNAc stimulation is beneficial and is a potential new therapeutic target for septic shock in young.