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HIF?1? attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia?reperfusion injury in a rat MCAO model.

ABSTRACT: Hypoxia?inducible factor?1? (HIF?1?) is a key transcriptional factor in response to hypoxia and is involved in ischemic stroke. In the present study, the potential for HIF?1? to inhibit neuronal apoptosis through upregulating erythropoietin (EPO) was investigated in a transient middle cerebral artery occlusion (tMCAO) rat stroke model. For this purpose, a recombinant adenovirus expressing HIF?1? was engineered (Ad?HIF?1?). Control adenovirus (Ad group), Ad?HIF?1? (Ad?HIF?1? group) or Ad?HIF?1? in addition to erythropoietin mimetic peptide?9 (EMP9), an EPO?receptor (?R) antagonist (Ad?HIF?1?+EMP9 group), were used for an intracranial injection into rat ischemic penumbra 1 h following MCAO. All rats demonstrated functional improvement following tMCAO, while the improvement rate was faster in rats treated by Ad?HIF?1? compared with all other groups. The EPO?R inhibitor partially reversed the benefits of Ad?HIF?1?. Apoptosis induced by tMCAO was significantly inhibited by Ad?HIF?1? (P<0.05). The expression of HIF?1?, evaluated by immunohistochemistry either in neurons or astrocytes, was upregulated by Ad?HIF?1?. Both EPO mRNA and protein expression were increased by Ad?HIF?1?, however, there was no significant change of EPO?R either on an mRNA level or protein level. Furthermore, EMP9 did not change the EPO expression which was upregulated by Ad?HIF?1?. Activated caspase 3 in neurons was suppressed by Ad?HIF?1?. Activated caspase 3 downregulated by HIF?1? was partially blocked by EMP9. Altogether, the present data demonstrated that HIF?1? attenuates neuronal apoptosis partially through upregulating EPO following cerebral ischemia in rat. Thus, upregulating HIF?1? subsequent to a stroke may be a potential treatment for ischemic stroke.

SUBMITTER: Li J

PROVIDER: S-EPMC7053873 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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HIF‑1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia‑reperfusion injury in a rat MCAO model.

Li Jun J Tao Tao T Xu Jian J Liu Zhi Z Zou Zhehua Z Jin Minglu M

International journal of molecular medicine 20200128 4

Hypoxia‑inducible factor‑1α (HIF‑1α) is a key transcriptional factor in response to hypoxia and is involved in ischemic stroke. In the present study, the potential for HIF‑1α to inhibit neuronal apoptosis through upregulating erythropoietin (EPO) was investigated in a transient middle cerebral artery occlusion (tMCAO) rat stroke model. For this purpose, a recombinant adenovirus expressing HIF‑1α was engineered (Ad‑HIF‑1α). Control adenovirus (Ad group), Ad‑HIF‑1α (Ad‑HIF‑1α group) or Ad‑HIF‑1α i ...[more]

PMID: 32124933

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Project description:Stroke and subsequent cerebral ischemia/reperfusion (I/R) injury is a frequently occurring disease that can have serious consequences in the absence of timely intervention. Circular RNAs (circRNAs) in association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression. However, whether circRNAs have a role in cerebral I/R injury pathogenesis, especially soon after onset, is unclear. In this study, we used the SD rat middle cerebral artery occlusion (MCAO) model of stroke to examine the role of circRNAs in cerebral I/R injury. We used high-throughput sequencing (HTS) to compare the expression levels of circRNAs in cerebral cortex tissue from MCAO rats during the occlusion-reperfusion latency period 3 hours after I/R injury with those in control cerebral cortices. Our sequencing results revealed that expression levels of 44 circRNAs were significantly altered after I/R, with 16 and 28 circRNAs showing significant up- and down-regulation, respectively, relative to levels in control cortex. We extended these results in vitro in primary cultured neuron cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) using qRT-PCR to show that levels of circ-camk4 were increased in OGD/R neurons relative to control neurons. Bioinformatics analyses predicted that several miRNAs could be associated with circ-camk4 and this prediction was confirmed in a RNA pull-down assay. KEGG analysis to predict pathways that involve circ-camk4 included the glutamatergic synapse pathway, MAPK signaling pathway, and apoptosis signaling pathways, all of which are known to be involved in brain injury after I/R. Our results also demonstrate that levels of the human homolog to circ-camk4 (hsa-circ-camk4) are elevated in SH-SY5Y cells exposed to OGD/R treatment. Overexpression of hsa-circ-camk4 in SH-SY5Y cells significantly increased the rate of cell death after OGD/R, suggesting that circ-camk4 may play a key role in progression of cerebral I/R injury.

Dataset Information

HIF?1? attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia?reperfusion injury in a rat MCAO model.

Publications

HIF‑1α attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia‑reperfusion injury in a rat MCAO model.

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