O-GlcNAc stimulation is beneficial in sepsis in the young rat, involvement of the ATP-citrate lyase

T Dupas,M Denis,A Persello,J Dontaine,L Bultot,A Erraud,J Dhot,T Pelé,A Leroux,E Bigot-Corbel,J Montnach,D Vertommen,J Lebreton,A Tessier,M Rivière,M De Waard,L Bertrand,B Rozec,B Lauzier

doi:10.1016/j.acvdsp.2021.04.140

Abstract

The young population, particularly at risk of septic shock, is rarely studied. The O-GlcNAcylation is a post-translational modification involved in cell survival, metabolism and stress response. We have shown that O-GlcNAc stimulation at the early phase of septic shock is beneficial in adult rats. Considering that O-GlcNAc levels are higher in the young, the impact of O-GlcNAc stimulation on sepsis in the young should be tested. Evaluate if O-GlcNAc stimulation could improve sepsis outcomes in young. Endotoxemic shock was induced in 28 days old rats by injection of LPS (O111 :B4, 20 mg.kg −1 –LPS) and compared to control rats (injection of saline–CTRL). One hour after LPS injection rats were randomly assigned to no therapy (LPS), fluidotherapy (saline, 10 mL.kg −1 –LPS + R) ± NButGT (10 mg.kg −1 –NButGT) to increase O-GlcNAc levels ( n = 11 per group). Physiological functions and plasmatic markers were evaluated 2 hours later. Impact of treatment was evaluated with an adapted Pediatric RISk of Mortality score (PRISM score) and mortality was evaluated over 36 hours ( n = 16 per group). Untargeted mass spectrometry was performed to identify cardiac O-GlcNAcylated proteins. LPS induced a shock (mean arterial pressure (MAP): CTRL: 67.2 ± 1.9; LPS: 50.7 ± 2.1 mmHg; P < 0.05), altered biological parameter (lactates: CTRL: 3.92 ± 0.26; LPS: 6.42 ± 0.45 mmol.L −1 ; P < 0.05) and PRISM score ( P < 0.05). LPS + R has no beneficial effect while NButGT improves MAP ( P < 0.05), PRISM score ( P < 0.05) and the median survival (NButGT: 36.0; LPS + R: 13.65; hours; P < 0.001). Most of proteins identified by mass spectrometry (60 %) are involved in the metabolism. Strinckingly, the ATP-citrate lyase (ACLY) is the only protein less O-GlcNAcylated in the NButGT group. O-GlcNAc stimulation acutely improves outcome in young septic shock rat. The impact of O-GlcNAcylation on ACLY is a potential issue to decipher the role of this protein during sepsis.

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