Connection between cardiac vascular permeability, myocardial oedema and inflammation during sepsis: role of the alpha1AMPK isoform

Objective: Since AMP-activated protein kinase (AMPK) both controls cytoskeletonorganization in endothelial cells (ECs) and exerts anti-inflammatory effects, we here
postulated that it could influence vascular permeability and inflammation, thereby
counteracting cardiac wall oedema during sepsis.
Design: Controlled animal study
Settings: University research laboratory
Subjects: C57BL/6J, α1AMPK-/- and α1AMPK+/+ mice
Intervention: Sepsis was triggered in vivo using a sub-lethal injection of
lipopolysaccharide (LPS, O55B5, 10 mg.kg-1), inducing systolic left ventricular (LV)
dysfunction. LV function, oedema, vascular permeability and inflammation were
assessed in vivo in both wild type (WT) mice (α1AMPK+/+) and α1AMPK-deficient
mice (α1AMPK-/-). 5-Aminoimidazole-4-carboxamide riboside (AICAr) served to study
the impact of AMPK activation on vascular permeability in vivo. The integrity of EC
monolayers was also examined in vitro after LPS challenge in the presence of AICAr
and/or after α1AMPK silencing.
Measurements and main results: α1AMPK-deficiency dramatically impaired tolerance
to LPS challenge. Indeed, α1AMPK-/- exhibited heightened cardiac vascular
permeability after LPS challenge compared to α1AMPK+/+. Consequently, an increase
in LV mass corresponding to exaggerated wall oedema occurred in α1AMPK-/-, without
any further decrease in systolic function. Mechanistically, the LPS-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, AMPK activation by AICAr counteracted LPS-induced
hyperpermeability in WT mice in vivo as well as in ECs in vitro. This effect was
associated with a potent protection of ZO-1 linear border pattern in ECs.
Conclusions: Our results demonstrate, for the first time the involvement of a signalling
pathway in the control of LV wall oedema during sepsis. AMPK exerts a protective
action through the preservation of interendothelial tight junctions. Interestingly,
exaggerated LV wall oedema was not coupled with aggravated systolic dysfunction.
However, it could contribute to diastolic dysfunction in septic patients.