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Beneficial cardiovascular effects of O‐GlcNAc increase in early phase of septic shock
Author(s) -
Ferron Marine,
Cadiet Julien,
Prat Valentine,
Erraud Angélique,
Aillerie Virginie,
Grabherr Amandine,
Mevel Mathieu,
Alraj Mohammed,
Chatham John,
Rozec Bertrand,
Gauthier Chantal,
Lauzier Benjamin
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1280.6
Subject(s) - lipopolysaccharide , septic shock , medicine , blood pressure , shock (circulatory) , ejection fraction , endocrinology , inflammation , mean arterial pressure , resuscitation , systemic inflammation , saline , sepsis , heart rate , anesthesia , heart failure
Background O‐GlcNAcylation, a post‐translational modification, is the end product of the hexosamine biosynthetic pathway (HBP). Recent studies showed that increased concentration of N‐acetylglucosamine has beneficial effects in acute pathologies, such as hemorrhagic shock. Objectives We postulated that the increase in O‐GlcNAc at the early phase of septic shock, a systemic inflammation associated with a cardiovascular dysfunction, could improve the cardiovascular function. Methods Endotoxemic shock was induced in rats (n=6–9) by iv injection of lipopolysaccharide (LPS, 5 mg/kg) or saline (CTRL). One hour later, fluid resuscitation (FR, 15 ml/kg of colloid, iv) was associated or not with HBP substrate (glucosamine, GlcN, 180 mg/kg, iv) or an O‐GlcNAcase inhibitor (NButGT, 10 mg/kg, iv). Two hours later, echocardiography and arterial blood pressure measures were performed. Then, heart and blood were collected to evaluate biological parameters, inflammation and autophagy. Results LPS rats presented a hypotension corrected by FR and O‐GlcNAc increase (mean arterial pressure: CTRL 87±1, LPS 73±5 * , LPS‐FR 93±6 # , LPS‐FR‐NButGT 83±5, LPS‐FR‐GlcN 92±4mmHg, * : p<0.01 vs CTRL, # : p<0.01 vs LPS). LPS rats also presented a decrease of ejection fraction by 21% and diastolic function (E/A ratio) by 29%. These parameters were normalised by NButGT and tended to be improved by GlcN. In LPS rats, plasmatic troponin T and lactate were significantly increased by 31 and 1.7‐fold respectively, they were normalised under NButGT and GlcN treatments. Interestingly, increase in O‐GlcNAc was not associated with modification of autophagic pathway (Beclin‐1, LC3, Lamp‐2) or inflammation (TNFα, IL‐6). Conclusions Our results suggest that the increase in total O‐GlcNAc at the early phase of septic shock could be a suitable therapeutic strategy. However, it remains to be determined which cellular pathways are modulated by the O‐GlcNAc increase.