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Hypoxic postconditioning activates the Wnt/β-catenin pathway and protects against transient global cerebral ischemia through Dkk1 Inhibition and GSK-3β inactivation.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2019 Aug; Vol. 33 (8), pp. 9291-9307. Date of Electronic Publication: 2019 May 23. - Publication Year :
- 2019
-
Abstract
- The Wingless/Int (Wnt)/β-catenin pathway plays an essential role in cell survival. Although postconditioning with 8% oxygen can alleviate transient global cerebral ischemia (tGCI)-induced neuronal damage in hippocampal CA1 subregion in adult rats as demonstrated by our previous studies, little is understood about the role of Wnt/β-catenin pathway in hypoxic postconditioning (HPC)-induced neuroprotection. This study tried to investigate the involvement of Wnt/β-catenin pathway in HPC-induced neuroprotection against tGCI and explore the underlying molecular mechanism thereof. We observed that HPC elevated nuclear β-catenin level as well as increased Wnt3a and decreased Dickkopf-1 (Dkk1) expression in CA1 after tGCI. Accordingly, HPC enhanced the expression of survivin and reduced the ratio of B-cell lymphoma/lewkmia-2 (Bcl-2)-associated X protein (Bax) to Bcl-2 following reperfusion. Moreover, our study has shown that these effects of HPC were abolished by lentivirus-mediated overexpression of Dkk1, and that the overexpression of Dkk1 completely reversed HPC-induced neuroprotection. Furthermore, HPC suppressed the activity of glycogen synthase kinase-3β (GSK-3β) in CA1 after tGCI, and the inhibition of GSK-3β activity with SB216763 increased the nuclear accumulation of β-catenin, up-regulated the expression of survivin, and reduced the ratio of Bax to Bcl-2, thus preventing the delayed neuronal death after tGCI. Finally, the administration of LY294002, an inhibitor of PI3K, increased GSK-3β activity and blocked nuclear β-catenin accumulation, thereby decreasing survivin expression and elevating the Bax-to-Bcl-2 ratio after HPC. These results suggest that activation of the Wnt/β-catenin pathway through Dkk1 inhibition and PI3K/protein kinase B pathway-mediated GSK-3β inactivation contributes to the neuroprotection of HPC against tGCI.-Zhan, L., Liu, D., Wen, H., Hu, J., Pang, T., Sun, W., Xu, E. Hypoxic postconditioning activates the Wnt/β-catenin pathway and protects against transient global cerebral ischemia through Dkk1 inhibition and GSK-3β inactivation.
- Subjects :
- Animals
Blotting, Western
Brain Ischemia genetics
CA1 Region, Hippocampal metabolism
Glycogen Synthase Kinase 3 beta genetics
Immunohistochemistry
Intercellular Signaling Peptides and Proteins genetics
Male
Proto-Oncogene Proteins c-bcl-2 genetics
Rats
Rats, Wistar
Wnt Proteins genetics
beta Catenin genetics
Brain Ischemia metabolism
Glycogen Synthase Kinase 3 beta metabolism
Intercellular Signaling Peptides and Proteins metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Wnt Proteins metabolism
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 33
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 31120770
- Full Text :
- https://doi.org/10.1096/fj.201802633R