Altered extracellular vesicle microrna expression in ischemic stroke and small vessel disease

van Kralingen, J., McFall, A. , Ord, E. N.J. , Coyle, T. F., Bissett, M., McClure, J. D. , McCabe, C. , Macrae, I. M., Dawson, J. and Work, L. M. (2019) Altered extracellular vesicle microrna expression in ischemic stroke and small vessel disease. Translational Stroke Research, 10(5), pp. 495-508. (doi: 10.1007/s12975-018-0682-3) (PMID:30617992) (PMCID:PMC6733813)

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Active transport of microRNAs (miRNA) in extracellular vesicles (EV) occurs in disease. Circulating EV-packaged miRNAs in the serum of stroke patients were compared to stroke mimics with matched cardio- and cerebrovascular risk factors, with corroboration of results in a pre-clinical model. An unbiased miRNA microarray was performed in stroke vs stroke mimic patients (n=39). Results were validated (n=173 patients) by real-time quantitative polymerase chain reaction. miRNA expression was quantified in total serum/EV (n=5-7) of naïve adult spontaneously hypertensive stroke-prone rats (SHRSP), their normotensive reference strain (Wistar Kyoto, WKY) and in circulating EV (n=3), peri-infarct brain (n=6) or EV derived from this region (n=3) in SHRSP following transient middle cerebral artery occlusion (tMCAO). Circulating EV concentration did not differ between stroke and stroke mimic patients. The microarray identified many altered EV-packaged miRNAs: levels of miRNA-17-5p, -20b-5p and -93-5p (miRNA-17 family members) and miRNA-27b-3p were significantly (p≤0.05) increased in stroke vs stroke mimic patients. Patients with small vessel disease (SVD) consistently had the highest miRNA levels. Circulating EV concentration was unaltered between naïve SHRSP and WKY but levels of miRNA-17-5p and -93-5p were significantly increased in SHRSP. tMCAO in SHRSP did not further alter circulating EV miRNA-17 family member expression and nor did it change total miRNA-17 family levels in peri-infarct brain tissue or in EV isolated from this region at 24hrs post-tMCAO. Changes in EV packaged miRNA expression was validated in patients with stroke, particularly those with SVD, and corroborated pre-clinically. Together, altered circulating EV levels of miRNA-17 family members may reflect the chronic sequelae underlying cerebrovascular SVD rather than the acute ischemic stroke itself.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McCabe, Dr Chris and McFall, Dr Aisling and Macrae, Professor Mhairi and Ord, Dr Emily and Van Kralingen, Ms Josie and Work, Dr Lorraine and Dawson, Professor Jesse and McClure, Dr John
Authors: van Kralingen, J., McFall, A., Ord, E. N.J., Coyle, T. F., Bissett, M., McClure, J. D., McCabe, C., Macrae, I. M., Dawson, J., and Work, L. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Translational Stroke Research
ISSN (Online):1868-601X
Published Online:07 January 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Translational Stroke Research 10(5):495-508
Publisher Policy:Reproduced under a Creative Commons License
Data DOI:10.5525/gla.researchdata.717

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
606411MRC Doctoral Training Grant 2012-16Margaret MacLeanMedical Research Council (MRC)MR/K500847/1 DTGRI CARDIOVASCULAR & MEDICAL SCIENCES
571821Modulation of miRNA as a therapeutic strategy for strokeLorraine WorkMedical Research Council (MRC)G1100562RI CARDIOVASCULAR & MEDICAL SCIENCES
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES