Benjamin Lauzier, Bertrand Rozec, Chantal Gauthier


The primary objective of our group is to improve patient outcome in shock situation. Taking advantage of our in vivo and ex vivo technics, such as isolated working heart, PV loop, high throughput screening technics, we have been developing new concept to develop treatment for acute cardiac decompensation during shock. We have a particular focus on O-GlcNAc, a particular post-translational modification involved in cell response to stress and metabolic modification.

  • hErOiSmE project

Shock situations (whether hemorrhagic or septic) share common pathophysiological mechanisms (implementation of inflammatory processes, cardiovascular failures, hypoperfusion of peripheral organs, etc.) that require rapid and appropriate management. They are both associated with high morbidity and mortality with a cost to society that increases each year. Unfortunately, the available treatments are very limited and mainly target symptoms. All recent studies have failed, we are facing a therapeutic impasse. It is therefore urgent to develop new strategies for new targets. In this context, our project aim to develop new approaches. In collaboration with JC Chatham (University of Birmingham, Alabama, US), we have developed an approach to stimulate O-GlcNAcylation in hemorrhagic shock or septic shock. O-GlcNAcylation is a post-translational modification responsible for cell survival that plays a major role in the cell response to stress. The approaches developed by our two teams aim to increase O-GlcNAc levels very early on, and are associated with a significant reduction in stress markers, an improvement in cardiovascular function and a significant reduction in mortality in both types of shock. These studies demonstrate that the stimulation of O-GlcNAcylation has significant therapeutic potential for patient survival and on the battlefield to limit the damage associated with shock situations.

The consortium, supported by the ANR, has been built with the chemists of the Ceisam team (univ Nantes), JC Chatham and our team IIb will enable us to develop a stable molecule, injectable intramuscularly or intravenously with targeting properties. With this funding, we hope to ensure its safety and validate its efficacy at different times / dose in order to quickly offer injectable treatment to patients and on the battlefield to reduce the morbidity and mortality associated with hemorrhagic and septic shock.

  • O-GlcNac as a new target for cardiac decompensation

O-GlcNAc is a post-translational modification with a central in cellular homeostasis, yet its role is not fully understood. We have built a consortium (Luc Bertrand, UCL, Belgium, Tarik Issad, Cochin Paris, Yan Burelle and Christine Des Rosiers Canada, Emilie Camberlein, Nantes) of researchers interested in this particular post-translational modification to decipher the role of this modification in pathophysiological condition. We have demonstrated in rat that this modification is strongly modified during the post-natal development in rat and we are building a cohort of samples from patient (CHANCE) of different age to validate this observation in human. Our data strongly suggest that this modification is of potential interest in many acute situations.

  • Preclinical development

Thanks to a collaboration with Inflectis Biosciences we have developed a model a extracorporeal circulation to study the impact of SIRS (systemic inflammatory response syndrome) on cardiovascular function to develop new treatments.

Publications

Protein O-GlcNAcylation levels are regulated independently of dietary intake in a tissue and time-specific manner during rat postnatal development.
Dupas T, Denis M, Dontaine J, Persello A, Bultot L, Erraud A, Vertommen D, Bouchard B, Tessier A, Rivière M, Lebreton J, Bigot-Corbel E, Montnach J, De Waard M, Gauthier C, Burelle Y, Olson AK, Rozec B, Des Rosiers C, Bertrand L, Issad T, Lauzier B.
Acta Physiol (Oxf) 2020 Oct 6;e13566

O-GlcNAc stimulation: A new metabolic approach to treat septic shock.
Ferron M, Cadiet J, Persello A, Prat V, Denis M, Erraud A, Aillerie V, Mevel M, Bigot E, Chatham JC, Gauthier C, Rozec B, Lauzier B.
Sci Rep. 2019 Dec 10;9(1):18751.

β1-Adrenergic cardiac contractility is increased during early endotoxemic shock: Involvement of cyclooxygenases.
Roul D, Rozec B, Ferron M, Erfanian M, Persello A, Audigane L, Grabherr A, Erraud A, Merlet N, Guijarro D, Muramatsu I, Lauzier B, Gauthier C.
Life Sci. 2019 Nov 1;236:116865.

Protein O-GlcNAcylation in Cardiac Pathologies: Past, Present, Future.
Ferron M, Denis M, Persello A, Rathagirishnan R, Lauzier B.
Front Endocrinol (Lausanne). 2019 Jan 15;9:819.

AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation.
Gélinas R, Mailleux F, Dontaine J, Bultot L, Demeulder B, Ginion A, Daskalopoulos EP, Esfahani H, Dubois-Deruy E, Lauzier B, Gauthier C, Olson AK, Bouchard B, Des Rosiers C, Viollet B, Sakamoto K, Balligand JL, Vanoverschelde JL, Beauloye C, Horman S, Bertrand L.
Nat Commun. 2018 Jan 25;9(1):374.

Study of intrinsic cardiac dysfunction in septic shock conditions by isolated working heart: a primary approach before new therapeutic proposals?
M Ferron, V Prat, D Roul, J Cadiet, C Gauthier, B Rozec, B Lauzier.
SM Emergency Medicine and Critical Care, Juillet 2017.

Funding

This programme has been financed by :
 
  • Agence Nationale pour la Recherche
  • Région des Pays de la Loire
  • SFAR
  • BAXTER
  • Inflectis biosciences
  • DGA
  • Genavie
  • Sauve Ton Cœur