title: Hypoxia increases Nrf2-induced HO-1 expression via the PI3K/Akt pathway.
abstract: 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.
authors.affiliation: Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing City, 400038, P.R. China.
authors.forename: Ranzun
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing City, 400038, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing City, 400038, P.R. China, heguoxiang_tmmu@163.com.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D034741:RNA, Small Interfering; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt