Journal
NEUROBIOLOGY OF DISEASE
Volume 63, Issue -, Pages 184-193Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2013.11.023
Keywords
MicroRNA; HGTD-P; Brain; Hypoxia-ischemia; Apoptosis
Categories
Funding
- Major State Basic Research Development Program [2013CB967404]
- National Science Foundation of China [81330016, 31171020]
- Ministry of Education of China [313037, 20110181130002]
- State Commission of Science Technology of China [2012BAI04B04]
- Science and Technology Bureau of Sichuan Province [2010SZ0280, 2011 JTD0005]
- Ministry of Health of China [1311200003303)]
- Program for Outstanding Young Scholars of Sichuan University [2012SCU04B03]
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Human growth transformation dependent protein (HGTD-P) is a newly identified protein that promotes neuronal apoptosis in hypoxia-ischemia brain damage (HIBD) in neonatal rats. However, the mechanisms regulating HGTD-P expression are not clear. Here we describe microRNAs targeted to HGTD-P and examine their effects on regulating neuronal apoptosis in HIBD. We use samples from cultured neurons after oxygen-glucose deprivation (OGD) and postnatal day 10 rat brains after hypoxia-ischemia (HI). RT-PCR, Western blotting, and immunostaining are used to detect the expression of HGTD-P and cleaved caspase 3, as well as real-time PCR detects microRNA expression. MicroRNA agomir is used to inhibit the expression of HGTD-P, and DAN, TUNEL, and TTC staining are employed to detect cell apoptosis and brain damage. Moreover, in vitro processing assay is used to examine the mechanism by which HI down-regulates miR-139-5p expression. We found that miR-139-5p is down-regulated in neurons and rat brains after HI treatment. The expression pattern of miR-139-5p correlates inversely with that of HGTD-P. Furthermore, miR-139-5p agomir inhibits neuronal apoptosis and attenuates HIBD, which is concurrent with down-regulation of HGTD-P. Moreover, pre-miR-139 processing activity decreases in extracts from OGD neurons, and OGD neuronal extracts attenuates the processing of pre-miR-139 by Dicer. In conclusion, HI induces inhibitors which block the processing step of pre-miR-139, resulting in the down-regulation of mature miR-139-5p. The down-regulation of miR-139-5p plays a critical role in the upregulation of HGTD-P expression. MiR-139-5p agomir attenuates brain damage when used 12 h after HI, providing a longer therapeutic window than anti-apoptosis compounds currently available. (C) 2013 Elsevier Inc. All rights reserved.
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