Highlights
- •NDRG2 is highly expressed in the plasma of IS patients.
- •Low expression of mTOR is identified in plasma of IS patients.
- •The PI3K/Akt/mTOR pathway is impaired by NDRG2 via dephosphorylation.
- •Blockage of NDRG2 inhibits neuronal apoptosis and autophagy.
- •BEZ235 reverses the inhibitory effect of sh-NDRG2 on neuronal apoptosis and autophagy.
Abstract
Background
Astrocytic N-myc downstream-regulated gene 2 (NDRG2), a differentiation- and stress-associated
molecule, has been involved in the cause of ischemic stroke (IS). However, its downstream
effector in IS remains unclear. This study aimed to characterize expression of NDRG2
in IS patients and rats and to investigate the underlying mechanism.
Methods
The protein expression of NDRG2 and mammalian target of the rapamycin (mTOR) and the
extent of mTOR phosphorylation in plasma of IS patients were detected by ELISA. An
oxygen-glucose deprivation model was established in mouse neuronal cells CATH.a, followed
by cell counting kit-8, flow cytometry, TUNEL, and western blot assays to examine
cell viability, apoptosis and autophagy. Finally, the effect of NDRG2-mediated phosphatidylinositol
3-kinase/protein kinase-B/mTOR (PI3K/AKT/mTOR) pathway on neuronal apoptosis and autophagy
was verified in rats treated with middle cerebral artery occlusion.
Results
NDRG2 was highly expressed in the plasma of IS patients, while the extent of mTOR
phosphorylation was reduced in IS patients. NDRG2 blocked the PI3K/Akt/mTOR signaling
through dephosphorylation. Depletion of NDRG2 suppressed apoptosis and autophagy in
CATH.a cells, which was reversed by a dual inhibitor of PI3K and mTOR, BEZ235. In vivo experiments confirmed that NDRG2 promoted neuronal apoptosis and autophagy by dephosphorylating
and blocking the PI3K/Akt/mTOR signaling.
Conclusion
The present study has shown that NDRG2 impairs the PI3K/Akt/mTOR pathway via dephosphorylation
to promote neuronal apoptosis and autophagy in IS. These findings provide potential
targets for future clinical therapies for IS.
Keywords
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Article info
Publication history
Published online: January 16, 2023
Accepted:
January 9,
2023
Received in revised form:
December 28,
2022
Received:
October 27,
2022
Identification
DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2023.106984
Copyright
© 2023 Elsevier Inc. All rights reserved.
