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

Accumulating evidence indicates that transient hypoxic preconditioning improves resistance to severe hypoxia and enhances the therapeutic potential of endothelial progenitor cells (EPCs) in cell-based therapies for vascular repair and ischemic disease; however, the mechanisms underlying this process remain unclear. This study aimed to test the hypothesis that hypoxic preconditioning activates nuclear factor E2-related factor 2 (Nrf2) and expression of its target genes, resulting in improved biological function and resistance to hypoxia. Exposure to hypoxia following small interfering RNA (siRNA)-mediated knockdown of Nrf2 resulted in increased apoptosis and impaired proliferation and angiogenesis in vitro as a result of activation of nuclear translocation of Nrf2 by the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway and subsequent increase in expression of the Nrf2 target gene, heme oxygenase 1 (HO-1). Moreover, the hypoxia-induced secretion of hypoxia-inducible factor 1-alpha (HIF-1 alpha) 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 is mediated via the PI3K/Akt-Nrf2-HO-1 signaling pathway, and the secretion of HIF-1 alpha followed by Nrf2 activation.