Caspase-1 is hepatoprotective through up-regulation of autophagy after hemorrhagic shock (169.20)

Abstract

Abstract Hemorrhagic shock induces tissue hypoxia, cellular oxidative stress and production of reactive oxygen species, which we have previously shown leads to activation of the inflammasome and caspase-1. Our previous data also show that caspase-1 is hepatoprotective after hemorrhagic shock/resuscitation (HS/R). Autophagy is a protective response to cellular stress and we hypothesized that caspase-1 is hepatoprotective by regulating autophagy after HS/R. Autophagic markers beclin1 were upregulated in WT liver after HS/R but to significantly lower levels in caspase-1-/- liver, and caspase-1-/- liver also had higher levels of apoptosis. Adenovirus encoding beclin1 (Adbeclin1) or control AdGFP was injected via tail vein in WT and caspase-1-/- mice. After 48h mice were subjected to HS/R. Immunoblotting of whole liver lysates confirmed beclin1 overexpression after Adbeclin1. Caspase-1-/- mice expressing Adbeclin1 had significantly less liver injury after HS/R and lower cytochrome c release (marker of apoptosis/mitochondrial damage) compared with AdGFP-caspase-1-/- mice and similar to WT levels. Similarly, in vitro primary hepatocytes isolated from caspase-1 -/- mice had decreased beclin1 expression, reduced autophagic flux and increased cells death after hypoxia/reoxygenation compared with WT cells. Together our data suggest that upregulation of beclin1 is vital for hepatoprotection after HS/R and that caspase-1 regulates beclin1 expression and autophagy through a novel pathway.