Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

Marine Angé; Julien De Poortere; Audrey Ginion; Sylvain Battault; Mélanie Dechamps; Giulio G. Muccioli; Martin Roumain; Johann Morelle; Sébastien Druart; Thomas Mathivet; Luc Bertrand; Diego Castanares-Zapatero; Sandrine Horman; Christophe Beauloye

doi:10.1038/s41598-021-93156-1

Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

Marine Angé, Julien De Poortere, Audrey Ginion, Sylvain Battault, Mélanie Dechamps, Giulio G. Muccioli, Martin Roumain, Johann Morelle, Sébastien Druart, Thomas Mathivet, Luc Bertrand, Diego Castanares-Zapatero, Sandrine Horman, Christophe Beauloye

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

Résumé

Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.

langue originale	Anglais
Numéro d'article	13700
journal	Scientific Reports
Volume	11
Numéro de publication	1
Les DOIs	https://doi.org/10.1038/s41598-021-93156-1
Etat de la publication	Publié - déc. 2021
Modification externe	Oui

Financement

This research work was supported by grants from Fonds National de la Recherche Scientifique et Médicale (FNRS, Belgium) and Action de Recherche Concertée de la Communauté Wallonie-Bruxelles, Belgium (ARC 13/18-051, ARC 16/21-074). MA was supported by a FRIA fellowship (FNRS, Belgium) and Bourse du Patrimoine (UCLou-vain, Belgium). SH works as a senior research associate at FNRS, Belgium.

Bailleurs de fonds	Numéro du bailleur de fonds
Action de Recherche Concertée de la Communauté Wallonie-Bruxelles
Bourse du Patrimoine
Fonds National de la Recherche Scientifique et Médicale
UCLou-vain
Australian Government, Australian Research Council	13/18-051
Fonds de la Recherche Scientifique F.R.S.-FNRS
Fonds pour la Formation à la Recherche dans l'Industrie et l'Agriculture

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Angé, M., De Poortere, J., Ginion, A., Battault, S., Dechamps, M., Muccioli, G. G., Roumain, M., Morelle, J., Druart, S., Mathivet, T., Bertrand, L., Castanares-Zapatero, D., Horman, S., & Beauloye, C. (2021). Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK. Scientific Reports, 11(1), Article 13700. https://doi.org/10.1038/s41598-021-93156-1

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title = "Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK",

abstract = "Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad{\textquoteright}s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.",

author = "Marine Ang{\'e} and {De Poortere}, Julien and Audrey Ginion and Sylvain Battault and M{\'e}lanie Dechamps and Muccioli, {Giulio G.} and Martin Roumain and Johann Morelle and S{\'e}bastien Druart and Thomas Mathivet and Luc Bertrand and Diego Castanares-Zapatero and Sandrine Horman and Christophe Beauloye",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41598-021-93156-1",

language = "English",

volume = "11",

journal = "Scientific Reports",

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Angé, M, De Poortere, J, Ginion, A, Battault, S, Dechamps, M, Muccioli, GG, Roumain, M, Morelle, J, Druart, S, Mathivet, T, Bertrand, L, Castanares-Zapatero, D, Horman, S & Beauloye, C 2021, 'Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK', Scientific Reports, VOL. 11, Numéro 1, 13700. https://doi.org/10.1038/s41598-021-93156-1

TY - JOUR

T1 - Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

AU - Angé, Marine

AU - De Poortere, Julien

AU - Ginion, Audrey

AU - Battault, Sylvain

AU - Dechamps, Mélanie

AU - Muccioli, Giulio G.

AU - Roumain, Martin

AU - Morelle, Johann

AU - Druart, Sébastien

AU - Mathivet, Thomas

AU - Bertrand, Luc

AU - Castanares-Zapatero, Diego

AU - Horman, Sandrine

AU - Beauloye, Christophe

PY - 2021/12

Y1 - 2021/12

N2 - Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.

AB - Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.

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U2 - 10.1038/s41598-021-93156-1

DO - 10.1038/s41598-021-93156-1

M3 - Article

C2 - 34211080

AN - SCOPUS:85109346005

SN - 2045-2322

VL - 11

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 13700

ER -

Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

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