PI3K/Akt signaling pathway-induced heme oxygenase-1 upregulation mediates the adaptive cytoprotection of hydrogen peroxide preconditioning against oxidative injury in PC12 cells

摘要

Both the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and heme oxygenase-1 (HO-1) create a survival signal against oxidative stress-induced injuries. Although we have demonstrated that hydrogen peroxide (H 2O 2) preconditioning confers adaptive cytoprotection against oxidative stress-induced injury in PC12 cells, it remains unknown whether these defense systems are involved in the protective effect of H 2O 2 preconditioning. In the current study, PC12 cells were preconditioned with 100 μM H 2O 2 for 90 min, followed by 24 h recovery and subsequent exposure to 300 μM H 2O 2 for further 12 h. The findings showed that preconditioning with 100 μM H 2O 2 upregulated HO-1 expression. Zinc protoporphyrin IX (ZnPP), a selective inhibitor of HO-1, at a concentration of 15 μM, significantly attenuated H 2O 2 preconditioning-elicited cytotoxicity, apoptosis, oxidative stress and mitochondrial membrane potential (ΔΨm) loss in PC12 cells. In addition, H 2O 2 preconditioning enhanced phosphorylation of Akt. Treatment with 25 μM LY294002, a selective inhibitor of PI3K, for 20 min before H 2O 2 preconditioning blocked not only H 2O 2 preconditioning-induced HO-1 induction, but also the protective effect of H 2O 2 preconditioning against cytotoxicity. The present study provides novel evidence for the effect of preconditioning with H 2O 2 on the induction of HO-1, which contributes to the adaptive cytoprotection of H 2O 2 preconditioning against oxidative stress-induced cellular injury via a PI3K/Akt-dependent mechanism in PC12 cells.