title: miR-15b suppression of Bcl-2 contributes to cerebral ischemic injury and is reversed by sevoflurane preconditioning.
abstract: Ischemic neuroprotection afforded by sevoflurane preconditioning has been previously demonstrated, yet the underlying mechanism is poorly understood and likely affects a wide range of cellular activities. Several individual microRNAs have been implicated in both the pathogenesis of cerebral ischemia and cellular survival, and are capable of affecting a range of target mRNA. Conceivably, sevoflurane preconditioning may lead to alterations in ischemia-induced microRNA expression that may subsequently exert neuroprotective effects. We first examined the microRNA expression profile following transient cerebral ischemia in rats and the impact of sevoflurane preconditioning. Microarray analysis revealed that 3 microRNAs were up-regulated (>2.0 fold) and 9 were down-regulated (< 0.5 fold) following middle cerebral artery occlusion (MCAO) compared to sham controls. In particular, miR-15b was expressed at significantly high levels after MCAO. Preconditioning with sevoflurane significantly attenuated the upregulation of miR-15b at 72h after reperfusion. Bcl-2, an anti-apoptotic gene involved in the pathogenesis of cerebral ischemia, has been identified as a direct target of miR-15b. Consistent with the observed downregulation of miR-15b in sevoflurane-preconditioned brain, postischemic Bcl-2 expression was significantly increased by sevoflurane preconditioning. We identified the 3'-UTR of Bcl-2 as the target for miR-15b. Molecular inhibition of miR-15b was capable of mimicking the neuroprotective effect of sevoflurane preconditioning, suggesting that the suppression of miR-15b due to sevoflurane contributes to its ischemic neuroprotection. Thus, sevoflurane preconditioning may exert its anti-apoptotic effects by reducing the elevated expression of miR-15b following ischemic injury, allowing its target proteins, including Bcl-2, to be translated and expressed at the protein level.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shi
authors.forename: Bao-liang
authors.initials: BL
authors.lastname: Sun
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.forename: Shiduo
authors.initials: S
authors.lastname: Lu
authors.forename: Pengyue
authors.initials: P
authors.lastname: Zhang
authors.forename: Hailian
authors.initials: H
authors.lastname: Wang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yu
authors.forename: R Anne
authors.initials: RA
authors.lastname: Stetler
authors.forename: Peter S
authors.initials: PS
authors.lastname: Vosler
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
mesh_terms: D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics*; D057967:Infusions, Intraventricular; D002546:Ischemic Attack, Transient / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D019194:Ischemic Preconditioning; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000494:pharmacology*; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D000077149:Sevoflurane; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D001549:Benzamides; D008738:Methyl Ethers; D035683:MicroRNAs; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C515128:TW-37 compound; C534110:mirn15 microRNA, rat; D000077149:Sevoflurane