Hypoxia increases Nrf2-induced HO-1 expression via the PI3K/Akt pathway

Accumulating evidence indicates that transient hypoxic preconditioning improves the resistance of endothelial progenitor cells (EPCs) to severe hypoxia and enhances the therapeutic potential of EPC-based therapies used in vascular repair and ischemic disease. However, the mechanisms underlying these processes remain unknown. This study tested the hypothesis that hypoxic preconditioning activates nuclear factor E2-related factor 2 (Nrf2) and the expression of its target genes, which improves biological functioning and resistance to hypoxia. Exposure to hypoxia after small interfering RNA (siRNA)-mediated knockdown of Nrf2 resulted in increased apoptosis, impaired proliferation, and angiogenesis in vitro. These changes were due to the activation of Nrf2 nuclear translocation via the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and subsequent increase in the expression of the Nrf2 target gene heme oxygenase 1 (HO-1). Moreover, the hypoxia-induced secretion of hypoxia-inducible factor 1-α (HIF-1α) in EPCs was inhibited by Nrf2 siRNA. In conclusion, the increased resistance to hypoxia and improved therapeutic potential of EPCs, as a result of hypoxia preconditioning, are mediated by the PI3K/Akt-Nrf2-HO-1 signaling pathway and the secretion of HIF-1α after Nrf2 activation.