http://stroke.ahajournals.org/content/early/2018/05/31/STROKEAHA.118.020627?platform=hootsuite
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Abstract
Background and Purpose—Social
isolation increases mortality and impairs recovery after stroke in
clinical populations. These detrimental effects have been recapitulated
in animal models, although the exact mechanism mediating these effects
remains unclear. Dysregulation of microRNAs (miRNAs) occurs in both
strokes as well as after social isolation, which trigger changes in many
downstream genes. We hypothesized that miRNA regulation is involved in
the detrimental effects of poststroke social isolation in aged animals.
Methods—We
pair-housed 18-month-old C57BL/6 male mice for 2 weeks before a
60-minute right middle cerebral artery occlusion or sham surgery and
then randomly assigned mice to isolation or continued pair housing
immediately after surgery. We euthanized mice either at 3, 7, or 15 days
after surgery and isolated the perilesional frontal cortex for whole
microRNAome analysis. In an additional cohort, we treated mice 1 day
after stroke onset with an in vivo-ready antagomiR-141 for 3 days.
Results—Using
whole microRNAome analysis of 752 miRNAs, we identified miR-141-3p as a
unique miRNA that was significantly upregulated in isolated mice in a
time-dependent manner up to 2 weeks after stroke. Posttreatment with an
antagomiR-141-3p reduced the postisolation-induced increase in
miR-141-3p to levels almost equal to those of pair-housed stroke
controls. This treatment significantly reduced mortality (by 21%) and
normalized infarct volume and neurological scores in poststroke-isolated
mice. Quantitative PCR analysis revealed a significant upregulation of
Tgfβr1 (transforming growth factor beta receptor 1, a direct target of
miR-141-3p) and Igf-1 (insulin-like growth factor 1) mRNA after
treatment with antagomiR. Treatment also increased the expression of
other pleiotropic cytokines such as Il-6 (interleukin 6) and Tnf-α
(tumor necrosis factor-α), an indirect or secondary target) in brain
tissue.
Conclusions—miR-141-3p
is increased with poststroke isolation. Inhibition of miR-141-3p
improved mortality, neurological deficits, and decreased infarct
volumes. Importantly, these therapeutic effects occurred in aged
animals, the population most at risk for stroke and poststroke
isolation.
- Received January 4, 2018.
- Revision received April 19, 2018.
- Accepted April 25, 2018.
- © 2018 American Heart Association, Inc.
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