Canonical notch pathway protects hepatocytes from ischemia/reperfusion injury in mice by repressing reactive oxygen species production through JAK2/STAT3 signaling.

UNLABELLED

Hepatic ischemia/reperfusion (I/R) injury is initiated by reactive oxygen species (ROS) accumulated during the early reperfusion phase after ischemia, but cellular mechanisms controlling ROS production and scavenging have not been fully understood. In this study, we show that blocking Notch signal by knockout of the transcription factor RBP-J or a pharmacological inhibitor led to aggravated hepatic I/R injury, as manifested by deteriorated liver function and increased apoptosis, necrosis, and inflammation, both in vitro and in vivo. Interruption of Notch signaling resulted in increased intracellular ROS in hepatocytes, and a ROS scavenger cured exacerbated hepatic I/R injury after Notch signaling blockade, suggesting that Notch signal deficiency aggravated I/R injury through increased ROS levels. Notch signal blockade resulted in down-regulation of Hes5, leading to reduced formation of the Hes5-STAT3 complex and hypophosphorylation of STAT3, which further attenuated manganese superoxide dismutase (MnSOD) expression and increased ROS and apoptosis. Indeed, overexpression of a constitutively active STAT3 rescued MnSOD expression and I/R injury-induced apoptosis in the absence of Notch signaling. Finally, forced Notch activation by ligand stimulation or Hes5 overexpression reduced intracellular ROS and protected hepatocytes from apoptosis after I/R injury through the activation of STAT3 and MnSOD expression.

CONCLUSION

Notch signal protects hepatocytes from I/R injury by Hes5-dependent activation of STAT3, which activates the expression of MnSOD, leading to the scavenging of ROS.