Modulation of carbonic anhydrase activity with O-GlcNacylation stimulation: A new approach to prevent post-cardiopulmonary bypass multi-organ dysfunction

O-GlcNAcylation is a post-translational modification involved in stress response. Its stimulation is beneficial in states of shock in murine models with a potential impact on carbonic anhydrase (CA). Cardiopulmonary bypass (CPB) share common pathophysiological mechanism and the cardiovascular alteration associated with remain untreated. Evaluate the impact of (i) O-GlcNAc levels in human and (ii) the impact of O-GlcNAc stimulation during extracorporeal circulation (ECC) and the impact on CA function in rat. A biocollection of human blood samples in adults (n = 36) and children (n = 23) during CPB central venous placement, aortic declamping, 5–6 and 12 hours after declamping. After being anesthetized 24 rats were randomly assigned to receive no therapy, 1-hour ECC or ECC + NButGT to increase O-GlcNAc levels and evaluated 5 hours after ECC weaning. Proteins O-GlcNAcylation and CA levels were evaluated by Western-blot. CA activity was assessed 1 h after treatment on 18 rats receiving NButGT or not. In adults and children undergoing cardiac surgery, CPB was associated with an increase in blood O-GlcNAc levels 6 hours (+29% and +27% respectively P < 0.05) after declamping. ECC model induced multi-organ dysfunction. Treatment with NButGT restored physiological performances: mean arterial pressure at H + 5 (ECC: 70 ± 8 mmHg; ECC + NButGT: 94 ± 7 mmHg; P < 0.05), lactate level at H + 5 (ECC: 3.9 ± 0.9 mmol/L; ECC + NButGT: 1.7 ± 0.2 mmol/L P = 0.08), creatininemia level at H + 5 (ECC: 1.48 ± 0.15 mg/dL; ECC + NButGT: 0.87 ± 0.05 P < 0.0001), and reduced severity score (ECC: 9 ± 0.7; ECC + NButGT: 2 ± 1; P < 0.001). Rats treated with NButGT had a lower CA quantity (−34% P < 0.001), ratio between CA activity and quantity showed higher activity (+62%; P < 0.001) (Fig. 1). Increase in O-GlcNAc level after CPB seems to be a response to stress. Results obtained with O-GlcNAc stimulation in the rat model suggest that this could be a promising strategy for the management of perioperative complication through modulation of CA activity.