title: Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size.
abstract: 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.
authors: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
authors: Savita
authors: S
authors: Khanna
authors: Cameron
authors: C
authors: Rink
authors: Reza
authors: R
authors: Ghoorkhanian
authors: Surya
authors: S
authors: Gnyawali
authors: Mallory
authors: M
authors: Heigel
authors: Dayanjan S
authors: DS
authors: Wijesinghe
authors: Charles E
authors: CE
authors: Chalfant
authors: Yuk Cheung
authors: YC
authors: Chan
authors: Jaideep
authors: J
authors: Banerjee
authors: Yue
authors: Y
authors: Huang
authors: Sashwati
authors: S
authors: Roy
authors: Chandan K
authors: CK
authors: Sen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000235:genetics* / Q000473:pathology*; D016923:Cell Death / Q000235:genetics* / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000235:genetics* / Q000473:pathology*; D015777:Eicosanoids / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005978:Glutathione / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D011247:Pregnancy; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020521:Stroke / Q000235:genetics* / Q000473:pathology*; D024508:Tocotrienols / Q000494:pharmacology; D014162:Transfection
chemical_list: D000975:Antioxidants; D015777:Eicosanoids; C547014:MIRN29 microRNA, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D024508:Tocotrienols; D012313:RNA; D001092:Arachidonate 12-Lipoxygenase; D005978:Glutathione
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