Castanares Zapatero, Diego
[UCL]
Sepsis is the main cause of mortality in non-coronary intensive care units. Its severity arises from the presence of organ dysfunction. Induced capillary leakage contributes to organ dysfunction during sepsis. However, the contribution of cardiac oedema to sepsis-induced left ventricular dysfunction remains to be clarified. In addition, signalling pathways controlling the sepsis-induced myocardial oedema has not been identified. Since AMP-activated protein kinase (AMPK) has been shown to control endothelial cytoskeleton and to display anti-inflammatory effects, we postulated that APMK-activation influenced vascular permeability and inflammation during sepsis even in the heart and could modulate heart function during severe sepsis. In our model, sepsis was mimicked with lipopolysaccharide (LPS) injection in vivo in a murine model and in vitro on cultured-endothelial monolayer. The major findings of this work is that the alpha-1 isoform of AMPK controls myocardial vascular permeability and is involved during sepsis. α1AMPK-/- animals exhibited a dramatic increased in the LPS-induced vascular hyperpermeability within the heart. In addition, survival after lipopolysaccharide injection was lower in α1AMPK-/- animals. We observed by echocardiography and magnetic resonance imaging an increase in LV mass 24 h after LPS injection in α1AMPK-/- animals. Despite the more pronounced wall oedema in α1AMPK-/- animals, no difference in systolic function could be detected after LPS. However, inverse relationship between left ventricular end-diastolic volume and LV mass highly suggest a more important diastolic function. These phenomena occurred independentlty from the inflammatory response. The observed mechanism was a disruption of interendothelial junctions and more particularly Zonula occludens-1 in the tight junctions. Treatment with the AMPK activator, AICAriboside, reduced the LPS-induced vascular hyperpermeability and restored interendothelial junctions in vivo and in vitro. AMPK could consequently represent a new pharmacological target because it mediates endothelial dysfunction and hyperpermeability.


Bibliographic reference |
Castanares Zapatero, Diego. Connection between cardiac vascular permeability, myocardial oedema and inflammation during sepsis : role of AMP-activated kinase. Prom. : Beauloye, Christophe ; Laterre, Pierre-François |
Permanent URL |
http://hdl.handle.net/2078.1/135811 |