Beneficial Effects of O-GlcNAc Stimulation in a Young Rat Model of Sepsis: Beyond Modulation of Gene Expression

Abstract

The young population, which is particularly at risk of sepsis, is, paradoxically, rarely studied. Acute stimulation of O-GlcNAcylation, a post-translational modification involved in metabolic regulation, cell survival and stress response, is beneficial in young rats with sepsis. Considering that sepsis impacts the gene expression profile and that O-GlcNAcylation is a regulator of transcription, the aims of this study are to (i) unveil beneficial mechanisms of O-GlcNAcylation and (ii) decipher the relationship between O-GlcNAcylation and transcription during sepsis. Endotoxemic challenge was induced in 28-day-old male rats using a lipopolysaccharide injection (E. coli O111:B4, 20 mg·kg−1) and compared to control rats (NaCl 0.9%). One hour after, rats were assigned to no therapy or fluidotherapy (NaCl 0.9%, 10 mL.kg−1) ± NButGT (10 mg·kg−1) to stimulate O-GlcNAc levels. Cardiac O-GlcNAcylation levels were evaluated via Western blot and gene transcription using 3′ SRP analysis. Lipopolysaccharide injection favorizes inflammatory state with the overexpression of genes involved in the NF-κB, JAK/STAT and MAPK pathways. NButGT treatment increased cardiac O-GlcNAcylation levels (p < 0.05). Yet, the mRNA expression was not impacted two hours after fluidotherapy or NButGT treatment. In conclusion, O-GlcNAc stimulation-induced beneficial effects are not dependent on the gene expression profile at the early phase of sepsis.

NButGT Reinforces the Beneficial Effects of Epinephrine on Cardiac Mitochondrial Respiration, Lactatemia and Cardiac Output in Experimental Anaphylactic Shock

“…Due to its good efficiency and specificity, NbutGT blocks directly the active site of OGA to maintain a high level of protein O-GlcNAcylation [ 18 ]. NbutGT is shown to act as a direct competitive inhibitor of OGA without impacting transcriptome [ 26 ]. Dupas et al [ 27 ] did not report any impact of NbutGT on the gene expression profile in an experimental model of septic shock, whereas the O-GlcNAcylome was modified by NbutGT treatment.…”

Epigenetic mechanisms of Immune remodeling in sepsis: targeting histone modification

“…Similarly, O-GlcNAc stimulation was also found to improve the prognosis in young rats with sepsis, and O-GlcNAcylated proteins are mainly correlated with cellular metabolism [ 84 ]. Whereas, this beneficial impact of O-GlcNAc is independent of changes in gene profile expression at the early stages of sepsis [ 85 ]. A recent study has illustrated an O-GlcNAcylation-mediated mechanism of innate immune regulation in sepsis progress.…”

Integration of O-GlcNAc into Stress Response Pathways

“…Among these were heat shock proteins (HSP70, HSP27), mitochondrial respiratory subunits, metabolic enzymes (Protein disulfide-isomerase A4 and ATP-citrate synthase), and components of the contractile apparatus and cytoskeleton (Tubulin alpha, Troponin C, Lamin A) [ 149 ]. Finally, a transcriptomic analysis of this model revealed differential expression of genes participating in mitogen-activated protein kinase (MAPK), NF-κB and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways [ 150 ]. However, while these pathways were strongly impacted by LPS endotoxemic stress, they were not affected by NButGT treatment.…”

“…However, while these pathways were strongly impacted by LPS endotoxemic stress, they were not affected by NButGT treatment. One explanation is that the short window of OGA inhibition (2 h, NButGT) does not sufficiently capture early O-GlcNAc-related changes in gene expression [ 150 ]. Together, these studies highlight a beneficial role of O-GlcNAcylation in septic shock and imply that its beneficial effects in the early phase are likely attributable to direct O-GlcNAcylation on diverse cardiac proteins across multiple different functional classes.…”