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

Abstract

Rationale 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. Objectives 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. Methods 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\xa0mg.kg-1) and 1\xa0h after, fluidotherapy (LPS\xa0+\xa0R)\xa0±\xa0NButGT (NButGT-10\xa0mg.kg-1). 2\xa0h later, physiological function (arterial blood pressure, heart and respiratory rate) and plasmatic markers of severity were measured. Results 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\xa0±\xa01,9; LPS: 50,7\xa0±\xa02,1\xa0mmHg; P\xa0 Conclusion 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.