MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury

Authors

Qingyi Ma, Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.Follow
Chiranjib Dasgupta, Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.Follow
Yong Li, Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.Follow
Lei Huang, Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.Follow
Lubo Zhang, Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.Follow

Document Type

Article

Publication Date

6-24-2017

Publication Title

International journal of molecular sciences

E-ISSN

1422-0067

Abstract

Cerebral edema, primarily caused by disruption of the blood-brain barrier (BBB), is one of the serious complications associated with brain injury in neonatal hypoxic-ischemic encephalopathy (HIE). Our recent study demonstrated that the hypoxic-ischemic (HI) treatment significantly increased microRNA-210 (miR-210) in the neonatal rat brain and inhibition of miR-210 provided neuroprotection in neonatal HI brain injury. The present study aims to determine the role of miR-210 in the regulation of BBB integrity in the developing brain. miR-210 mimic was administered via intracerebroventricular injection (i.c.v.) into the brain of rat pups. Forty-eight hours after the injection, a modified Rice-Vannucci model was conducted to produce HI brain injury. Post-assays included cerebral edema analysis, western blotting, and immunofluorescence staining for serum immunoglobulin G (IgG) leakage. The results showed that miR-210 mimic exacerbated cerebral edema and IgG leakage into the brain parenchyma. In contrast, inhibition of miR-210 with its complementary locked nucleic acid oligonucleotides (miR-210-LNA) significantly reduced cerebral edema and IgG leakage. These findings suggest that miR-210 negatively regulates BBB integrity i n the neonatal brain. Mechanistically, the seed sequences of miR-210 were identified complementary to the 3' untranslated region (3' UTR) of the mRNA transcripts of tight junction protein occludin and adherens junction protein β-catenin, indicating downstream targets of miR-210. This was further validated by in vivo data showing that miR-210 mimic significantly reduced the expression of these junction proteins in rat pup brains. Of importance, miR-210-LNA preserved the expression of junction proteins occludin and β-catenin from neonatal HI insult. Altogether, the present study reveals a novel mechanism of miR-210 in impairing BBB integrity that contributes to cerebral edema formation after neonatal HI insult, and provides new insights in miR-210-LNA mediated neuroprotection in neonatal HI brain injury.

Volume

18

Issue

7

DOI

10.3390/ijms18071356

PubMed ID

28672801

Recommended Citation

Ma, Qingyi; Dasgupta, Chiranjib; Li, Yong; Huang, Lei; and Zhang, Lubo, "MicroRNA-210 Suppresses Junction Proteins and Disrupts Blood-Brain Barrier Integrity in Neonatal Rat Hypoxic-Ischemic Brain Injury" (2017). Loma Linda University Faculty Publications. 336.
https://scholarsrepository.llu.edu/fac_pubs/336