O-GlcNAc stimulation is beneficial in septic shock models

Introduction Septic shock is a worldwide burden, without efficient treatments, killing one person every 3 s. Recently, O-GlcNAc stimulation (a post-translational modification) appeared to be beneficial in acute pathologies. Objective This study has been designed to evaluate if O-GlcNAc stimulation shows the same benefits in two relevant models of septic shock. Method Impact of NButGT (an OGlcNAcase inhibitor – 10 mg/kg) has been evaluated in LPS or CLP (caecal ligation and puncture) and their respective controls with or without fluidotherapy (FR). Cardiovascular function (mean arterial blood pressure (MAP), echocardiography) and biochemical markers (creatinine, lactates) were measured at 3 h and 24 h after shock induction respectively, then heart and blood were harvested to evaluate impact of the treatment. Also, O-GlcNAc impact on calcium actor was evaluated by western blot. LPS study was completed with a Kaplan–Meier mortality evaluation. Results NButGT treatments efficiently increased cardiac O-GlcNAc in both model (+300% vs. Ctrl or Sham). In both group, NButGT treatment induced an amelioration of the outcome and organs function specifically: cardiac (heart rate −9% vs. LPS; −10% vs. CLP), renal (creatinine −35% vs. LPS; −27% vs. CLP) and beneficial impact on blood pressure (MAP + 10% vs. CLP). Treatment had a significant impact on lactate in LPS group (−36% vs. LPS) consistent with a 3 times higher survival rate. Treatment impacted on SERCA2a protein (−150% vs. LPS, NS vs. ctrl) without modification of its regulator (phospholamban) or ryanodine receptor. Conclusion Our results support the fact that acute O-GlcNAc stimulation is a potential new therapeutic target at the early phase of septic shock. Potentially through improvement of cardiomyocytes’ calcium handling. We are currently validating our approach at different dose and age to be able to transfer our results to the clinic.