• Diego Castanares-Zapatero, Claire Bouleti, Caroline Sommereyns, Bernhard Gerber, Christelle Lecut, Thomas Mathivet, Michael Horckmans, Didier Communi, Marc Foretz, Jean-Louis Vanoverschelde, Stéphane Germain, Luc Bertrand, Pierre-François Laterre, Cecile Oury, Benoit Viollet, Sandrine Horman, and Christophe Beauloye.
• 1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium. 2Division of Intensive Care, Cliniques Universitaires Saint Luc, Brussels, Belgium. 3Center for Interdisciplinary Research in Biology, INSERM U1050, CNRS UMR7241, Collège de France, Paris, France. 4Division of Cardiology, Cliniques Universitaires Saint Luc, Brussels, Belgium. 5Laboratory of Thrombosis and Hemostasis, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium. 6Institute of Interdisciplinary Research in Human and Molecular Biology, Université Libre de Bruxelles, Brussels, Belgium. 7INSERM U1016, Institut Cochin, Paris, France. 8CNRS, UMR8104, Paris, France. 9Université Paris Descartes, Sorbonne Paris Cité, France.
• Crit. Care Med.. 2013 Dec 1;41(12):e411-22.

ObjectiveAs adenosine monophosphate (AMP)-activated protein kinase both controls cytoskeleton organization in endothelial cells and exerts anti-inflammatory effects, we here postulated that it could influence vascular permeability and inflammation, thereby counteracting cardiac wall edema during sepsis.DesignControlled animal study.SettingsUniversity research laboratory.SubjectsC57BL/6J, α1AMPK, and α1AMPK mice.InterventionSepsis was triggered in vivo using a sublethal injection of lipopolysaccharide (O55B5, 10 mg/kg), inducing systolic left ventricular dysfunction. Left ventricular function, edema, vascular permeability, and inflammation were assessed in vivo in both wild-type mice (α1AMPK) and α1AMP-activated protein kinase-deficient mice (α1AMPK). The 5-aminoimidazole-4-carboxamide riboside served to study the impact of AMP-activated protein kinase activation on vascular permeability in vivo. The integrity of endothelial cell monolayers was also examined in vitro after lipopolysaccharide challenge in the presence of aminoimidazole-4-carboxamide riboside and/or after α1AMP-activated protein kinase silencing.Measurements And Main Resultsα1AMP-activated protein kinase deficiency dramatically impaired tolerance to lipopolysaccharide challenge. Indeed, α1AMPK exhibited heightened cardiac vascular permeability after lipopolysaccharide challenge compared with α1AMPK. Consequently, an increase in left ventricular mass corresponding to exaggerated wall edema occurred in α1AMPK, without any further decrease in systolic function. Mechanistically, the lipopolysaccharide-induced α1AMPK cardiac phenotype could not be attributed to major changes in the systemic inflammatory response but was due to an increased disruption of interendothelial tight junctions. Accordingly, AMP-activated protein kinase activation by aminoimidazole-4-carboxamide riboside counteracted lipopolysaccharide-induced hyperpermeability in wild-type mice in vivo as well as in endothelial cells in vitro. This effect was associated with a potent protection of zonula occludens-1 linear border pattern in endothelial cells.ConclusionsOur results demonstrate for the first time the involvement of a signaling pathway in the control of left ventricular wall edema during sepsis. AMP-activated protein kinase exerts a protective action through the preservation of interendothelial tight junctions. Interestingly, exaggerated left ventricular wall edema was not coupled with aggravated systolic dysfunction. However, it could contribute to diastolic dysfunction in patients with sepsis.

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