Downregulation of miR-338-3p alleviates neuronal ischemic injury by decreasing cPKCγ-Mediated autophagy through the Akt/mTOR pathway.

Abstract

Ischemic stroke is the leading cause of mortality and disability in aging populations. Dysregulation of microRNA is associated with the pathophysiology of ischemic brain injury. Previously, we found that miR-338-3p was prominently downregulated in OGD-treated neurons, which indicates that miR-338-3P potentially plays an important role in ischemic injury. Furthermore, we performed a bioinformatic analysis and found that conventional protein kinase cγ (cPKCγ), an important autophagy regulator, is a potential target of miR-338-3p, and it is upregulated in neurons after ischemic injury. Therefore, we speculated that miR-338-3P may play a role in neuronal autophagy associated with ischemic brain injury by regulating cPKCγ levels. In the present study, oxygen glucose deprivation was used to test this hypothesis. Our results show that miR-338-3p expression is prominently downregulated after OGD. Additionally, miR-338-3p knockdown attenuated ischemic injury and simultaneously reduced the microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, which contributes to neuronal survival after ischemia. Moreover, the cPKCγ protein level increased, and miR-338-3p recognized the 3'-untranslated region of the cPKCγ messenger RNA (mRNA) and negatively regulated the cPKCγ protein level by promoting the degradation of its mRNA. In addition, Lv-cPKCγ blocked the pri-miR-338-3p-induced decrease of the Akt and mammalian target of rapamycin (mTOR) phosphorylation levels, as well as the accompanying increase of the LC3-II/LC3-I ratio, thereby alleviating ischemic injury. This suggests that miR-338-3p downregulation following ischemic injury alleviates neuronal injury by targeting cPKCγ, thereby activating the Akt/mTOR signaling cascade and decreasing downstream autophagy. These results provide a potential therapeutic target for ischemic stroke.

• Authors: Haiping Wei, Zhifeng Peng, Jia Guo, Lixia Chen, Kangmei Shao
• Journal: Neurochemistry international (Neurochem Int) Vol. 154 Pg. 105279 (03 2022) ISSN: 1872-9754 [Electronic] England
• PMID: 35021067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Ltd.

Chemical References

• MIRN338 microRNA, human
• MicroRNAs
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Glucose

Topics

• Autophagy
• Down-Regulation
• Glucose (metabolism)
• Humans
• Ischemia (metabolism)
• MicroRNAs (genetics, metabolism)
• Neurons (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases (metabolism)