Research Paper Volume 11, Issue 11 pp 3585—3600

Blocking lncRNA H19-miR-19a-Id2 axis attenuates hypoxia/ischemia induced neuronal injury

Zhipeng Xiao 1, *, , Yongming Qiu 1, *, , Yingying Lin 1, , Rogelio Medina 2, , Sophie Zhuang 2, , Jared S. Rosenblum 2, , Jing Cui 2, , Zezhi Li 3, , Xiaohua Zhang 1, , Liemei Guo 1, ,

  • 1 Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
  • 2 Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, MD 20892, USA
  • 3 Department of Neurology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
* Equal contribution

received: February 24, 2019 ; accepted: May 24, 2019 ; published: June 5, 2019 ;

https://doi.org/10.18632/aging.101999
How to Cite

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

Abstract

Elevated expression of lncRNA H19 (H19) in the setting of hypoxia has been implicated as a promising therapeutic target for various cancers. However, little is known about the impact and underlying mechanism of H19 in ischemic brain stroke. This study found that H19 levels were elevated in the serum of stroke patients, as well as in the ischemic penumbra of rats with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and neuronal cells with oxygen glucose deprivation (OGD). Further, knockdown of H19 with siRNA alleviated cell apoptosis in OGD neuronal cells, and inhibition of H19 in MCAO/R rats significantly decreased neurological deficit, brain infarct volume and neuronal apoptosis. Lastly, with gain and loss of function studies, dual luciferase reported assay, RNA immunoprecipitation (RIP) and pull-down experiments, we demonstrated the dual competitive interaction of miR-19a with H19 and the 3’-UTR of Id2 mRNA, resulting in the identification of the H19-miR-19a-Id2 axis. With biological studies, we also revealed that H19-miR-19a-Id2 axis modulated hypoxia induced neuronal apoptosis. This study demonstrates that the identified H19-miR-19a-Id2 axis plays a critical role in hypoxia induced neuronal apoptosis, and blocking this axis may serve as a novel therapeutic strategy for ischemic brain injury.

Abbreviations

ceRNA: Competing endogenous RNA; H/I: Hypoxia/ischemia; HIF: Hypoxia inducible factor; Id2: Inhibitor of DNA binding/differentiation 2; IgG: Immunoglobulin G; LncRNAs: Long noncoding RNAs; MCAO/R: Middle cerebral artery occlusion/reperfusion; MRI: Magnetic resonance imaging; NIHSS: National institute of health stroke scale; OGD: Oxygen-glucose deprivation; qRT-PCR: Quantitative real-time polymerase chain reaction; RIP: RNA immunoprecipitation.