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Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats.

ABSTRACT: Because our recent studies have demonstrated that miR-122 decreased in whole blood of patients and in whole blood of rats following ischemic stroke, we tested whether elevating blood miR-122 would improve stroke outcomes in rats. Young adult rats were subjected to a temporary middle cerebral artery occlusion (MCAO) or sham operation. A polyethylene glycol-liposome-based transfection system was used to administer a miR-122 mimic after MCAO. Neurological deficits, brain infarction, brain vessel integrity, adhesion molecule expression and expression of miR-122 target and indirect-target genes were examined in blood at 24 h after MCAO with or without miR-122 treatment. miR-122 decreased in blood after MCAO, whereas miR-122 mimic elevated miR-122 in blood 24 h after MCAO. Intravenous but not intracerebroventricular injection of miR-122 mimic decreased neurological deficits and brain infarction, attenuated ICAM-1 expression, and maintained vessel integrity after MCAO. The miR-122 mimic also down-regulated direct target genes (e.g. Vcam1, Nos2, Pla2g2a) and indirect target genes (e.g. Alox5, Itga2b, Timp3, Il1b, Il2, Mmp8) in blood after MCAO which are predicted to affect cell adhesion, diapedesis, leukocyte extravasation, eicosanoid and atherosclerosis signaling. The data show that elevating miR-122 improves stroke outcomes and we postulate this occurs via downregulating miR-122 target genes in blood leukocytes.

SUBMITTER: Liu da Z

PROVIDER: S-EPMC4976655 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo identify the time dependent profiles of gene expression and featured co-expression network modules in peripheral blood of rats after middle cerebral artery occlusion (MCAO).MethodsMicroarray GSE119121 from GEO database was analyzed by R language to identify the significantly changed genes in peripheral blood at different time points (0, 1, 2, 3, 6 and 24 h) after MCAO. Gene expression patterns at different time courses were screened by STEM tools. Then, function annotation and pathway enrichment of differentially expressed genes (DEGs) were performed using the Gene Ontology (GO) database and the Kyoto Gene and Genomic Encyclopedia (KEGG) database. Depending on CEMiTool package, gene expression profile matrix was inputted into R to construct the co-expression networks and to analyze modules, and enrichment analysis was conducted to evaluate the correlation between the modules and different time points.ResultsComparing with gene at 0 h, the numbers of DEGs in peripheral blood at different time points after MCAO were 163 (1 h), 502 (2 h), 527 (3 h), 550 (6 h), and 75 (24 h), respectively. Moreover, a total of 38 gene expression patterns were enriched, and pattern 65 and pattern 34 were specifically up-regulated or down-regulated at 2-6 h. Hp, Nos2, P2ry10, and Klf12 were representative genes of these two models. The co-expression network module analysis showed that the gene status in the early acute phase (1-6 h) was positively correlated with the Module 2. Module 3 and Module 4 was positively correlated with phase phase 1-3 h and 2-6 h, respectively. Noteworthy, Module 6 gradually changed from positive correlation (0-2 h) to negative correlation (3-24 h) with the MCAO time course, and Module 6 was mainly related to viral response and innate immune response. The hub genes of Module 6 included Mx1, Mx2, and Rtp4.ConclusionsOur study has identified the featured genes and dynamic co-expression network modules in peripheral blood after acute ischemic stroke, which provides a potential basis for judging the onset time of ischemic stroke.

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Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats.

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