Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury
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ORIGINAL ARTICLE
Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury Sophie Casey 1,2,3 & Kate Goasdoue 4 & Stephanie M. Miller 4 & Gary P. Brennan 5 & Gary Cowin 6 & Adam G. O’Mahony 3 & Christopher Burke 7 & Boubou Hallberg 8 & Geraldine B. Boylan 1 & Aideen M. Sullivan 3 & David C. Henshall 5,9 & Gerard W. O’Keeffe 1,3 & Catherine Mooney 1,9,10 & Tracey Bjorkman 4 & Deirdre M. Murray 1,2 Received: 15 April 2020 / Accepted: 8 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs—miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR128—were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival. Keywords Hypoxic ischemic encephalopathy . miRNA . miR-181a . Biomarker . Piglet model . BMP signalling
Introduction
Highlights • Altered miRNAs are potential HIE markers, detectable in the first hour of life. • Altered miRNAs were found consistently in both humans and a porcine model. • These miRNAs are miRs 374a, 181b, 181a, 151a, 148a and 151a. • These are correlated with gold standard MRS markers of neonatal encephalopathy. • Inhibition of miR-181a may confer neuroprotection via the BMP signalling pathway. • miRNA biomarkers may allow timely diagnosis and therapeutic interventions for HIE. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02018-w) contains supplementary material, which is available to authorized users. * Sophie Casey [email protected] Extended author information available on the last page of the article
Neonatal hypoxic ischemic encephalopathy (HIE) is an acute brain injury caused by a hypoxic ischemic insult (HI) due to the disruption of ce
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