Abstract
Ischemic stroke, a major cause of death, is caused by occlusion of a blood vessel, resulting in significant reduction in regional cerebral blood flow. MiRNAs are a family of short noncoding RNAs (18–22 nts) and bind the 3′-UTR of their target genes to suppress the gene expression post-transcriptionally. In the present study, we report that miR-143 is down-regulated in rat neurones but highly expressed in astrocytes. In vivo middle cerebral artery occlusion (MCAO) and ex vivo oxygen-glucose deprivation (OGD) results showed that miR-143 was significantly induced by ischemia injury. Meanwhile, we observed suppression of glucose uptake and lactate product of rat brain and primary neurones after MCAO or OGD. The glycolysis enzymes hexokinase 2 (HK2), PKM2, and LDHA were inhibited by MCAO or OGD at protein and mRNA levels. In addition, overexpression of miR-143 significantly inhibited HK2 expression, glucose uptake, and lactate product. We report that HK2 is a direct target of miR-143. Importantly, restoration of HK2 in miR-143 overexpressing rat neurones recovered glucose uptake and lactate product. Our results demonstrated inhibition of miR-143 during OGD could protect rat neuronal cells from ischemic brain injury (IBI). In summary, the present study reveals a miRNA-mediated neuron protection during IBI, providing a new strategy for the development of therapeutic agents against IBI.
Highlights
Brain ischemic stroke, which is a major cause of death, ranks number 3 amongst all the causes of death, after cardiovascular disease and cancer [1]
MiR-143 was significantly down-regulated in neurones and microglia, but higher expression of miR-143 was observed in astrocytes (Figure 1A), suggesting that miR-143 might involve in the maintenance of neuron functions during ischemic brain injury (IBI)
To investigate the role of miR-143 in regulating IBI, we compared the expression levels of miR-143 in rat brain before and after transient middle cerebral artery occlusion (MCAO), which presents an efficient model of inducing reproducible transient or permanent ischemia of the middle cerebral artery
Summary
Brain ischemic stroke, which is a major cause of death, ranks number 3 amongst all the causes of death, after cardiovascular disease and cancer [1]. Ischemic stroke is caused by occlusion of a blood vessel, resulting in significant reduction in regional cerebral blood flow [2]. Brain damage arises from deprivation of oxygen and glucose due to blockage of local blood supply. Cerebral ischemia activates a series of signaling cascades which lead to neurones’ death [3]. It has been known that oxidative stress induced by cerebral ischemia is one of the major causes of the neuronal injury [4]. The pathophysiological mechanisms are not still under investigation. Revealing the molecular mechanism for ischemic injury is necessary to develop effective therapies
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