0311 : Beneficial systemic effects of O-GlcNAc stimulation in early phase of sepsis

Abstract

Septic shock is a worldwide burden with over 750 000 cases per years in the US only. This pathology, characterized by a systemic inflammation, is notably associated with a severe cardiovascular dysfunction. Recently, Hilgers et al showed beneficial cardiovascular effects of the O-GlcNAcylation (a post-translational modification) stimulation during pro-inflammatory conditions. In this context, we postulated that stimulation of the OGlcNacylation at the early phase of septic shock could improve cardiovascular function. Rats received ( iv ) either lipopolysaccharide (LPS, 5mg/kg) or saline. One hour after, fluid resuscitation (15ml/kg of colloid, iv ) was associated or not with glucosamine (GlcN, 180mg/kg) or an inhibitor of O-GlcNAcase, NbutGT (10mg/kg). Two hours later, heart and blood samples were collected to evaluate global cardiac proteins O-GlcNAcylation by western-blot, to evaluate blood biological parameters (lactate, troponin T, creatinin), respectively. NButGT and GlcN treatment increased total O-GlcNAc by 200 and 300% respectively, versus LPS with colloid rats. Those treatments produced an acidosis (lactate: saline 2.80±0.43, LPS 6.37±0.54, NButGT 3.01±0.26 mmol/L), an improvement of cardiac dysfuntion (troponin T: saline 6.17±1.15, LPS 117.40±48.81, NButGT 30.89±16.82, GlcN 54.59±32.08 mmol/L) as well as renal dysfunction (creatinine: saline 25.37±1.31, LPS 77.50±7.81, NButGT 33.67±5.10, GlcN 33.67±5,10μmol/L). These results demonstrate a distinct improvement of organ function (heart and kidney) with an O-GlcNAcylation stimulation during early phase of sepsis. This study must be completed by the analysis of vasomotricity and inflammation under the O-GlcNAcylation stimulation and to determine the underlying mechanisms and their influence on mortality.