O-GlcNAcylation, a post-translational modification, is the end product of the hexosamine biosynthetic pathway (HBP). Recent studies showed beneficial effects of its increase in acute pathologies, such as hemorrhagic shock. We postulated that increase in total protein OGlcNAcylation at the early phase of septic shock, a systemic inflammation associated with a cardiovascular dysfunction, could improve cardiovascular function and reduce mortality.
Methods
To induce an endotoxemic shock, rats (n=6-8) received iv either lipopolysaccharide (LPS, 5mg/kg) or saline (CTRL). After 1 h, fluid resuscitation (FR,15mL/kg of colloid, iv) was associated or not with HBP substrate: glucosamine (GlcN, 180mg/kg) or an O-GlcNAcase inhibitor (NButGT, 10mg/kg). Two hours later, echography and mean arterial pressure (MAP) evaluation were performed; blood samples and heart were then collected to evaluate biological parameters (lactate, troponin T) and total O-GlcNAcylation by western-blot.
Results
In vivo studies showed an hypotension in LPS restored by FR and treatments (MAP: CTRL 87±1, LPS 73±5*, LPS-FR 93±6#, NButGT 83±5, GlcN 92±4mmHg, *: p<0.01 vs CTRL, #: p<0.01 vs LPS) and a systolic dys-function in LPS with a trend toward an improvement by NButGT and GlcN (ejection fraction: CTRL 80±3, LPS 66±3*, LPS-FR 69±2, NButGT 74±2, GlcN 75±2%, *: p<0.01 vs CTRL). NButGT and GlcN efficiently increased total O-GlcNAc (200 and 300% respectively vs LPS-FR). This effect was associated with a reduced cardiomyocyte insult and tissue dysoxia.
Conclusions
At the early phase of septic shock NButGT and GlcN induce an increase in cardiac O-GlcNAcylation leading to improve tissue oxygenation and to reduce cardiac injury. These treatments trend to increase the cardiovascular function. Yet, coming studies will evaluate the effect of NButGT and GlcN on mortality.
