Benefits of O-GlcNAcylation stimulation on cardiac output in hemorrhagic shock

Abstract

Introduction

O-GlcNAcylation (O-GlcNAc) is a post-translational modification of cytoplasmic, nuclear and mitochondrial proteins that consists of the addition of a sugar, β-D-N-acetylglucosamine (or GlcNAc), to their serine and threonine residues. It is involved in many biological processes and appears to play an important role in the cell's response to stress and its survival.

Objective

The aim of this study was to evaluate whether stimulation of O-GlcNAcylation has a potential effect on hemodynamic parameters, during the early phase of hemorrhagic shock (HS), using NButGT an O-GlcNAcase inhibitor, to increase O-GlcNAc levels.

Method

Female large white pigs (35-42 kg) were subjected to a HS and trauma protocol induced via bilateral femur fractures and passively exsanguinated to 60% of their estimated total blood volume (ETBV) through the jugular catheter, and then randomly treated or not with NButGT (10 mg/kg). Other animals were retransfused with depleted blood (Whole blood group), and others were exposed only to anesthesia without trauma or bleeding (SHAM group). Invasive hemodynamic monitoring was performed using a pulse index continuous cardiac output (PiCCO) device. Blood samples were collected repeatedly as tissue samples after euthanasia. The time at which 40% of ETBV was drained was defined as the “T0” time. Treatment was injected a the end of exsanguination and 90 min after “T0”. The procedure was terminated 6 hours after “T0” (enthanasia of the animals).

Results

The proportion of animals who died prematurely without reaching the end of the procedure do not differ by group (P-value of χ² > 0.05). Cardiac output was higher in the NButGT group compared with the placebo group, 90 min after “T0” (< 0.05), and also 120 min after “T0”, but without statistical significance (Fig. 1). Shock index was lower in the NButGT group compared with the placebo group, 90 min after “T0” (P-value < 0.05), and also 120 min after “T0”, but without statistical significance.

Conclusion

Our results show that NButGT administration could be helpful in minimizing the collapse of cardiac output and the rise in Shock Index in the acute phase of hemorrhagic shock. To our knowledge, this is the first time such results have been reported in a large mammal model. Further experiments will now be carried out, such as the study of O-GlcNAc levels by Western blot in heart cells, to confirm its increase under NButGT action and O-GlcNAc dynamics in this context.