Research Paper Volume 11, Issue 14 pp 5108—5123

Activation of AK005401 aggravates acute ischemia/reperfusion mediated hippocampal injury by directly targeting YY1/FGF21

Hongzhi Wan 1, *, , Ying Yang 1, *, , Miao Li 1, , Xin Liu 1, , Yeying Sun 1, , Kexin Wang 2, , Chunxiang Zhang 3, , Qingyin Zheng 4, , Chaoyun Wang 5, ,

  • 1 School of Pharmacy, Binzhou Medical University, Yantai, P. R. China
  • 2 Third class of senior high school, NO.2 Middle School of Yantai Shandong, Yantai, P. R. China
  • 3 Department of Biomedical Engineering and Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA
  • 4 Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
  • 5 Hearing and Speech Institute, Binzhou Medical University, Yantai, P. R. China
* Equal contribution.

received: April 8, 2019 ; accepted: July 12, 2019 ; published: July 23, 2019 ;

https://doi.org/10.18632/aging.102106
How to Cite
This article has been corrected. See Correction. Aging (Albany NY). 2019; 11:9960-9960. https://doi.org/10.18632/aging.102458

Copyright © 2019 Wan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Ischemia exerts a negative impact on mitochondrial function, which ultimately results in neuronal damage via alterations in gene transcription and protein expression. Long non- coding RNAs (LncRNAs) play pivotal roles in the regulation of target protein expression and gene transcription. In the present study, we observed the effect of an unclassical LncRNA AK005401on ischemia/reperfusion (I/R) ischemia-mediated hippocampal injury and investigated the regulatory role of fibroblast growth factor 21 (FGF21) and Yin Yang 1 (YY1). C57Black/6 mice were subjected to I/R using the bilateral common carotid clip reperfusion method, and AK005401 siRNA oligos were administered via intracerebroventricular injection. HT22 cells were used to establish a model of oxygen-glucose deprivation/reoxygenation (OGD/R). We observed pathological morphology and mitochondrial structure. Neuronal apoptosis was evident. Cell activity, cell respiration, FGF21, YY1, and antioxidant capacity were evaluated. I/R or OGD/R significantly increased the expressions of AK005401and YY1 and decreased FGF21expression, which further attenuated the activation of PI3K/Akt, promoted reactive oxygen species (ROS) generation, and then caused mitochondria dysfunction and cell apoptosis, which were reversed by AK005401 siRNA oligos and were aggravated by overexpression of AK005401 and YY1. We conclude that AK005401/YY1/FGF21 signaling pathway has an important role in I/R-mediated hippocampal injury.

Abbreviations

LncRNAs: Long non-coding RNAs; I/R: ischemia/reperfusion; FGF21: fibroblast growth factor 21; YY1: Yin Yang 1; OGD/R: oxygen-glucose deprivation/reoxygenation; PI3K: phosphatidylinositide 3-kinases; Akt: Protein Kinase B; ROS: promoted reactive oxygen species; ATP: Adenosine triphosphate; Nrf2: nuclear factor like(erythroid-derived 2); TMS: total motor score; MTT: thiazolyl blue tetrazolium bromide/3-(4,5-Dimethyl-2-thiazolyl)-2,5- diphenyl- 2H-tetrazolium bromide; DAPI: 4′,6-diamidino-2- phenylindole; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; MDA: malondialdehyde; BCA: bicinchoninic acid; TUNEL: terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling; HE: hematoxylin and eosin; DCFH-DA: 2,7-dichlorodihydrofluorescein diacetate; qRT-PCR: Quantitative real-time polymerase chain reaction; OXPHOS: oxidative phosphorylation; DMEM: Dulbecco’s modified Eagle medium; FBS: fetal bovine serum; DMSO: Dimethyl sulfoxide; NC RNA oligos: negative control RNA oligos.