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microRNAs: innovative targets for cerebral ischemia and stroke - PubMed

Review

microRNAs: innovative targets for cerebral ischemia and stroke

Yi-Bing Ouyang et al. Curr Drug Targets. .

Abstract

Stroke is one of the leading causes of death and disability worldwide. Because stroke is a multifactorial disease with a short therapeutic window many clinical stroke trials have failed and the only currently approved therapy is thrombolysis. MicroRNAs (miRNA) are endogenously expressed noncoding short single-stranded RNAs that play a role in the regulation of gene expression at the post-transcriptional level, via degradation or translational inhibition of their target mRNAs. The study of miRNAs is rapidly growing and recent studies have revealed a significant role of miRNAs in ischemic disease. miRNAs are especially important candidates for stroke therapeutics because of their ability to simultaneously regulate many target genes and since to date targeting single genes for therapeutic intervention has not yet succeeded in the clinic. Although there are already quite a few review articles about miRNA in ischemic heart disease, much less is currently known about miRNAs in cerebral ischemia. This review summarizes current knowledge about miRNAs and cerebral ischemia, focusing on the role of miRNAs in ischemia, both changes in expression and identification of potential targets, as well as the potential of miRNAs as biomarkers and therapeutic targets in cerebral ischemia.

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Conflict of interest statement

The authors have no conflicting financial interests.

Figures

Fig. 1
Fig. 1

miRNA biogenesis and function

Fig. 2
Fig. 2

A. Diagram of cerebral ischemia induced cell death signaling cascade. B. Chaperone network and BCL2 family members control ER-mitochondria Ca2+ crosstalk (left) and protein import/sorting (right) at the mitochondrial associated ER membrane (MAM). C. miRNA can influence MAM and cell survival by targeting both the chaperone network and BCL2 family members. Abbreviations: OMM-mitochondrial outer membrane; IMM- mitochondrial inner membrane calcium binding proteins crt-calreticulin; cnx-calnexin; Sec protein import complex. Channels involved in calcium passage IP3R –inositol 1,4,5 trisphosphate receptor, VDAC- voltage dependent anion channel; Members of the HSP70 family are shown in shades of yellow (Hsp70, 75, 78); cyp-D cyclophilin-D; mtc mitocalcin; ANT adenine nucleotide translocase; TOM outermembrane translocase complex; TIM translocase complex of inner membrane; MCU mitochondrial calcium uniporter.

Fig. 3
Fig. 3

Expression of miR-181, GRP78 protein, and Grp78 mRNA at different reperfusion time points after 1 hour transient focal cerebral ischemia. A. miR-181a expression in ischemic core and penumbra at different durations of reperfusion after middle cerrebral artery occlusion in mice shows increased levels in core but decreased levels in the penumbra (PNBR). B. GRP78 protein decreases in the ischemic core and increases in the penumbra with increasing durations of reperfusion after MCAO. Quantitation by densitometry of westerns for each time point. C. Expression of Grp78 mRNA (RT-PCR) in ischemic core and penumbra increases with reperfusion time after MCAO. N=4 mice/group in all experiments. *P<0.05 by ANOVA and Newman-Keuls post hoc test. From [19].

Fig. 4
Fig. 4

Effect of miR-181 down-regulation on infarction after focal ischemia. A. Representative cresyl violet-stained coronal sections demonstrate a decreased infarct size in a representative miR-181a antagomir transfected brain compared with the brain of a mismatch (MM) miR-181a-antagomir-injected animal also subjected to middle cerebral artery occlusion. B. The graph shows quantification of the infarct size. N=7 mice/group. *P<0.01 compared to MM control by T-test. From [19].

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