Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126
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ORIGINAL ARTICLE
Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126 Fan Chen 1,2 & Yang Du 2,3 & Elga Esposito 2 & Yi Liu 1,2 & Shuzhen Guo 2 & Xiaoying Wang 2 & Eng H. Lo 2 & Changhong Xing 2 & Xunming Ji 1
Received: 28 August 2015 / Revised: 28 September 2015 / Accepted: 2 October 2015 # Springer Science+Business Media New York 2015
Abstract Emerging data suggest that exosomal microRNA (miRNA) may provide potential biomarkers in acute ischemic stroke. However, the effects of ischemia-reperfusion on total versus exosomal miRNA responses in circulating blood remain to be fully defined. Here, we quantified levels of miR-126 in whole serum versus exosomes extracted from serum and compared these temporal profiles against reperfusion and outcomes in a rat model of acute focal cerebral ischemia. First, in vitro experiments confirmed the vascular origin and changes in miR-126 in brain endothelial cultures subjected to oxygenglucose deprivation. Then in vivo experiments were performed by inducing permanent or transient focal cerebral ischemia in rats, and total serum and exosomal miR-126 levels were quantified, along with measurements of infarction and neurological outcomes. Exosomal levels of miR-126 showed a transient reduction at 3 h post-ischemia that appeared to normalize back close to pre-ischemic baselines after 24 h. There were no detectable differences in exosomal miR-126 responses in permanent or transient ischemia. Serum miR-126 levels appeared to differ in permanent versus transient ischemia. Significant reductions in serum miR-126 were detected at 3 h after permanent ischemia but not transient ischemia. By 24 h, serum miR-
* Changhong Xing [email protected] * Xunming Ji [email protected] 1
Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
2
Massachusetts General Hospital, Harvard Medical School, Boston, USA
3
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
126 levels were back close to baseline in both permanent and transient ischemia. Overall, there were no correlations between serum miR-126 and exosomal miR-126. This proof-of-concept study suggests that changes in serum miR-126 may be able to distinguish severe permanent ischemia from milder injury after transient ischemia. Keywords Focal cerebral ischemia . miR-126 . Exosome . Biomarker . Reperfusion injury
Introduction MicroRNAs (miRNAs) are endogenously expressed ∼22 nucleotides long, noncoding RNAs that control a wide spectrum of cellular function [1–3]. Although their mechanism of action is not yet completely understood, recent studies suggested that specific miRNAs could bind to target regions of certain genes to control their expression by either repression or activation of mRNA translation/transcription [4, 5]. A single miRNA can regulate thousands of downstream target genes and influence the entire gene networks and downstream protein synthesis [6–8]. It has been demonstrated that miRNAs play important r
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