Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size

J Cereb Blood Flow Metab. 2013 Aug;33(8):1197-206. doi: 10.1038/jcbfm.2013.68. Epub 2013 May 1.


Glutathione depletion and 12-lipoxygenase-dependent metabolism of arachidonic acid are known to be implicated in neurodegeneration associated with acute ischemic stroke. The objective of this study was to investigate the significance of miR-29 in neurodegeneration associated with acute ischemic stroke. Neural cell death caused by arachidonic acid insult of glutathione-deficient cells was preceded by a 12-lipoxygenase-dependent loss of miR-29b. Delivery of miR-29b mimic to blunt such loss was neuroprotective. miR-29b inhibition potentiated such neural cell death. 12-Lipoxygenase knockdown and inhibitors attenuated the loss of miR-29b in challenged cells. In vivo, stroke caused by middle-cerebral artery occlusion was followed by higher 12-lipoxygenase activity and loss of miR-29b as detected in laser-captured infarct site tissue. 12-Lipoxygenase knockout mice demonstrated protection against such miR loss. miR-29b gene delivery markedly attenuated stroke-induced brain lesion. Oral supplementation of α-tocotrienol, a vitamin E 12-lipoxygenase inhibitor, rescued stroke-induced loss of miR-29b and minimized lesion size. This work provides the first evidence demonstrating that loss of miR-29b at the infarct site is a key contributor to stroke lesion. Such loss is contributed by activity of the 12-lipoxygenase pathway providing maiden evidence linking arachidonic acid metabolism to miR-dependent mechanisms in stroke.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Arachidonate 12-Lipoxygenase / physiology
  • Blotting, Western
  • Brain Ischemia / genetics*
  • Brain Ischemia / pathology*
  • Cell Death / genetics*
  • Cell Death / physiology*
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebral Infarction / genetics*
  • Cerebral Infarction / pathology*
  • Eicosanoids / metabolism
  • Female
  • Fluorescent Antibody Technique
  • Glutathione / metabolism
  • Magnetic Resonance Imaging
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / physiology*
  • Neurons / pathology*
  • Pregnancy
  • RNA / biosynthesis
  • RNA / isolation & purification
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Stroke / genetics*
  • Stroke / pathology*
  • Tocotrienols / pharmacology
  • Transfection


  • Antioxidants
  • Eicosanoids
  • MIRN29 microRNA, mouse
  • MicroRNAs
  • RNA, Small Interfering
  • Tocotrienols
  • RNA
  • Arachidonate 12-Lipoxygenase
  • Glutathione