Title:miR-15b Suppression of Bcl-2 Contributes to Cerebral Ischemic Injury and is Reversed by Sevoflurane Preconditioning
Volume: 12
Issue: 3
Author(s): Hong Shi, Bao-liang Sun, Jia Zhang, Shiduo Lu, Pengyue Zhang, Hailian Wang, Qiong Yu, R. Anne Stetler, Peter S. Vosler, Jun Chen and Yanqin Gao
Affiliation:
Keywords:
Sevoflurane, preconditioning, cerebral ischemia, microRNA, Bcl-2.
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.