IMR Press / FBL / Volume 21 / Issue 2 / DOI: 10.2741/4395

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.


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

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1 Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing City, 400038, P.R. China
Academic Editor:Fei He
Front. Biosci. (Landmark Ed) 2016, 21(2), 385–396;
Published: 1 January 2016
(This article belongs to the Special Issue Cellular immunology and stem cell biology)

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.

Hypoxia Preconditioning
Endothelial Progenitor Cells
Nuclear Factor-E2-related factor 2
Heme Oxygenase-1
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