PP2A inhibition alleviates DCD liver damage during prolonged cold ischemia by interfering Drp1 translocation and ER stress.

Prolonged cold ischemia-warm reperfusion (PCI/WR) of donor livers is an independent risk factor for primary nonfunction (PNF) after liver transplantation (LT). Previous studies have demonstrated that may be related to hepatocyte apoptosis mediated by the abnormal mitochondrial division. In the present study, we report that PCI/WR up-regulated apoptotic signals in donation after circulatory death (DCD) rat livers after 24 h of cold ischemia, increased the expression of PP2A, Drp1 and CHOP, and led to caspase-induced apoptosis. Downregulation of PP2A attenuated PCI/WR-induced hepatocyte injury, improved liver function, and decreased the expression of Drp1 and CHOP. In particular, okadaic acid (OA) inhibited the translocation of Drp1 to mitochondria and the release of Cyt c into the cytoplasm. Further investigation found that inhibiting mitochondrial division or ER-stress could slightly reverse the apoptosis rate induced by PCI/WR, while not affecting PP2A expression in vivo or in vitro. These observations indicated that PP2A involved in the regulation of hepatocyte apoptosis after prolonged cold storage, possibly through inhibiting the expression of Drp1 and CHOP, as well as Drp1 translocation. Our results provide evidence that PP2A could be a potential target for therapeutic intervention of DCD livers subjected to prolonged cold ischemia.