Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Translational Stroke Research
Published in: Translational Stroke Research 6/2015

01-12-2015 | Original Article

Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126

Authors: Fan Chen, Yang Du, Elga Esposito, Yi Liu, Shuzhen Guo, Xiaoying Wang, Eng H. Lo, Changhong Xing, Xunming Ji

Published in: Translational Stroke Research | Issue 6/2015

Login to get access

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 oxygen-glucose 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-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.
Literature
1.
2.
3.
Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, et al. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 2001;106(1):23–34.CrossRefPubMed
4.
5.
Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A. 2008;105(5):1608–13.PubMedCentralCrossRefPubMed
6.
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. Prediction of mammalian microRNA targets. Cell. 2003;115(7):787–98.CrossRefPubMed
7.
Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol. 2004;5(9):R68.PubMedCentralCrossRefPubMed
8.
Lai M, Macleod M. MicroRNA--taking regulation of protein synthesis to another level. Cerebrovasc Dis. 2005;20(1):49–50. discussion.CrossRefPubMed
9.
Fiore R, Siegel G, Schratt G. MicroRNA function in neuronal development, plasticity and disease. Biochim Biophys Acta. 2008;1779(8):471–8.CrossRefPubMed
10.
Christensen M, Schratt GM. microRNA involvement in developmental and functional aspects of the nervous system and in neurological diseases. Neurosci Lett. 2009;466(2):55–62.CrossRefPubMed
11.
12.
13.
Sorensen SS, Nygaard AB, Nielsen MY, Jensen K, Christensen T. miRNA expression profiles in cerebrospinal fluid and blood of patients with acute ischemic stroke. Transl Stroke Res. 2014;5(6):711–8.CrossRefPubMed
14.
Dharap A, Bowen K, Place R, Li LC, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab. 2009;29(4):675–87.PubMedCentralCrossRefPubMed
15.
Selvamani A, Williams MH, Miranda RC, Sohrabji F. Circulating miRNA profiles provide a biomarker for severity of stroke outcomes associated with age and sex in a rat model. Clin Sci (Lond). 2014;127(2):77–89.CrossRef
16.
Sepramaniam S, Tan JR, Tan KS, DeSilva DA, Tavintharan S, Woon FP, et al. Circulating microRNAs as biomarkers of acute stroke. Int J Mol Sci. 2014;15(1):1418–32.PubMedCentralCrossRefPubMed
17.
Chevillet JR, Lee I, Briggs HA, He Y, Wang K. Issues and prospects of microRNA-based biomarkers in blood and other body fluids. Molecules. 2014;19(5):6080–105.CrossRefPubMed
18.
Smalheiser NR. Do Neural Cells Communicate with Endothelial Cells via Secretory Exosomes and Microvesicles? Cardiovasc Psychiatry Neurol. 2009;2009:383086.PubMedCentralCrossRefPubMed
19.
Wu L, Walas S, Leung W, Sykes DB, Wu J, Lo EH, et al. Neuregulin1-beta decreases IL-1beta-induced neutrophil adhesion to human brain microvascular endothelial cells. Transl Stroke Res. 2015;6(2):116–24.CrossRefPubMed
20.
Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun. 2011;2:180.PubMedCentralCrossRefPubMed
21.
Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000;20(12):1681–9.CrossRefPubMed
22.
Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15(2):261–71.PubMedCentralCrossRefPubMed
23.
24.
van Solingen C, Seghers L, Bijkerk R, Duijs JM, Roeten MK, van Oeveren-Rietdijk AM, et al. Antagomir-mediated silencing of endothelial cell specific microRNA-126 impairs ischemia-induced angiogenesis. J Cell Mol Med. 2009;13(8A):1577–85.PubMedCentralCrossRefPubMed
25.
Foerch C, Montaner J, Furie KL, Ning MM, Lo EH. Invited article: searching for oracles? Blood biomarkers in acute stroke. Neurology. 2009;73(5):393–9.PubMedCentralCrossRefPubMed
26.
27.
Ye P, Liu J, He F, Xu W, Yao K. Hypoxia-induced deregulation of miR-126 and its regulative effect on VEGF and MMP-9 expression. Int J Med Sci. 2014;11(1):17–23.PubMedCentralCrossRefPubMed
28.
Long G, Wang F, Li H, Yin Z, Sandip C, Lou Y, et al. Circulating miR-30a, miR-126 and let-7b as biomarker for ischemic stroke in humans. BMC Neurol. 2013;13:178.PubMedCentralCrossRefPubMed
29.
Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE. MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. J Am Soc Hypertens. 2014;8(6):368–75.CrossRefPubMed
30.
Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107(6):810–7.CrossRefPubMed
31.
Wei Y, Nazari-Jahantigh M, Neth P, Weber C, Schober A. MicroRNA-126, −145, and −155: a therapeutic triad in atherosclerosis? Arterioscler Thromb Vasc Biol. 2013;33(3):449–54.CrossRefPubMed
32.
Di Y, Lei Y, Yu F, Changfeng F, Song W, Xuming M. MicroRNAs expression and function in cerebral ischemia reperfusion injury. J Mol Neurosci. 2014;53(2):242–50.CrossRefPubMed
33.
Weiss JB, Eisenhardt SU, Stark GB, Bode C, Moser M, Grundmann S. MicroRNAs in ischemia-reperfusion injury. Am J Cardiovasc Dis. 2012;2(3):237–47.PubMedCentralPubMed
34.
Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A. 2008;105(5):1516–21.PubMedCentralCrossRefPubMed
35.
Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15(2):272–84.PubMedCentralCrossRefPubMed
36.
Meng S, Cao JT, Zhang B, Zhou Q, Shen CX, Wang CQ. Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. J Mol Cell Cardiol. 2012;53(1):64–72.CrossRefPubMed
37.
Ning M, Sarracino DA, Kho AT, Guo S, Lee SR, Krastins B, et al. Proteomic temporal profile of human brain endothelium after oxidative stress. Stroke. 2011;42(1):37–43.PubMedCentralCrossRefPubMed
38.
Guo S, Lo EH. Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke. 2009;40(3 Suppl):S4–7.PubMedCentralCrossRefPubMed
39.
Weng H, Shen C, Hirokawa G, Ji X, Takahashi R, Shimada K, et al. Plasma miR-124 as a biomarker for cerebral infarction. Biomed Res. 2011;32(2):135–41.CrossRefPubMed
40.
Liu XS, Chopp M, Zhang RL, Tao T, Wang XL, Kassis H, et al. MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One. 2011;6(8), e23461.PubMedCentralCrossRefPubMed
41.
Egea V, Schober A, Weber C. Circulating miRNAs: messengers on the move in cardiovascular disease. Thromb Haemost. 2012;108(4):590–1.CrossRefPubMed
42.
Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.CrossRefPubMed
43.
44.
Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012;119(3):756–66.PubMedCentralCrossRefPubMed
45.
Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10(12):1470–6.PubMedCentralCrossRefPubMed
46.
Taverna S, Amodeo V, Saieva L, Russo A, Giallombardo M, De Leo G, et al. Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells. Mol Cancer. 2014;13:169.PubMedCentralCrossRefPubMed
47.
Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685–94.CrossRefPubMed
48.
Zhang ZG, Chopp M. Promoting brain remodeling to aid in stroke recovery. Trends Mol Med. 2015;21(9):543–8.CrossRefPubMed
Metadata
Title
Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126
Authors
Fan Chen
Yang Du
Elga Esposito
Yi Liu
Shuzhen Guo
Xiaoying Wang
Eng H. Lo
Changhong Xing
Xunming Ji
Publication date
01-12-2015
Publisher
Springer US
Published in
Translational Stroke Research / Issue 6/2015
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-015-0429-3

Other articles of this Issue 6/2015

Translational Stroke Research 6/2015 Go to the issue

Commentary

Microglia/Macrophage Polarization After Experimental Intracerebral Hemorrhage

Original Article

An Outcome Model for Intravenous rt-PA in Acute Ischemic Stroke

Original Article

Characteristics of Cerebrovascular Injury in the Hyperacute Phase After Induced Severe Subarachnoid Hemorrhage

Original Article

Effect of APOE Gene Polymorphism on Early Cerebral Perfusion After Aneurysmal Subarachnoid Hemorrhage

Original Article

MicroRNA let-7e Is a Potential Circulating Biomarker of Acute Stage Ischemic Stroke

Review

A Systematic Research Review Assessing the Effectiveness of Pursuit Interventions in Spatial Neglect Following Stroke